A tug-of-war between driver and passenger mutations in cancer and other adaptive processes

Cancer progression is an example of a rapid adaptive process where evolving new traits is essential for survival and requires a high mutation rate. Precancerous cells acquire a few key mutations that drive rapid population growth and carcinogenesis. Cancer genomics demonstrates that these few 'driver' mutations occur alongside thousands of random 'passenger' mutations-a natural consequence of cancer's elevated mutation rate. Some passengers can be deleterious to cancer cells, yet have been largely ignored in cancer research. In population genetics, however, the accumulation of mildly deleterious mutations has been shown to cause population meltdown. Here we develop a stochastic population model where beneficial drivers engage in a tug-of-war with frequent mildly deleterious passengers. These passengers present a barrier to cancer progression that is described by a critical population size, below which most lesions fail to progress, and a critical mutation rate, above which cancers meltdown. We find support for the model in cancer age-incidence and cancer genomics data that also allow us to estimate the fitness advantage of drivers and fitness costs of passengers. We identify two regimes of adaptive evolutionary dynamics and use these regimes to rationalize successes and failures of different treatment strategies. We find that a tumor's load of deleterious passengers can explain previously paradoxical treatment outcomes and suggest that it could potentially serve as a biomarker of response to mutagenic therapies. Collective deleterious effect of passengers is currently an unexploited therapeutic target. We discuss how their effects might be exacerbated by both current and future therapies

Hierarchical Models for Relational Event Sequences

Interaction within small groups can often be represented as a sequence of events, where each event involves a sender and a recipient. Recent methods for modeling network data in continuous time model the rate at which individuals interact conditioned on the previous history of events as well as actor covariates. We present a hierarchical extension for modeling multiple such sequences, facilitating inferences about event-level dynamics and their variation across sequences. The hierarchical approach allows one to share information across sequences in a principled manner---we illustrate the efficacy of such sharing through a set of prediction experiments. After discussing methods for adequacy checking and model selection for this class of models, the method is illustrated with an analysis of high school classroom dynamics

Cities and State Fiscal Structure

The fiscal systems of cities are defined by the states in which they are located. These systems can create an environment that either allows municipalities to fund their share of resident needs and to thrive economically or constrains the ability of cities to balance budgets and deliver basic services. This report examines how the key components of these systems (fiscal authority, revenue reliance/capacity, state aid and tax and expenditure limitations) are structured across states

Feasibility Assessment of an EVA Glove Sensing Platform to Evaluate Potential Hand Injury Risk Factors

Injuries to the hands are common among astronauts who train for extravehicular activity (EVA). When the gloves are pressurized, they restrict movement and create pressure points during tasks, sometimes resulting in pain, muscle fatigue, abrasions, and occasionally more severe injuries such as onycholysis. A brief review of the Lifetime Surveillance of Astronaut Health's injury database reveals that 58% of total astronaut hand and arm injuries from NBL training between 1993 and 2010 occurred either to the fingernail, MCP, or fingertip. The purpose of this study was to assess the potential of using small sensors to measure force acting on the fingers and hand within pressurized gloves and other variables such as blood perfusion, skin temperature, humidity, fingernail strain, skin moisture, among others. Tasks were performed gloved and ungloved in a pressurizable glove box. The test demonstrated that fingernails saw greater transverse strain levels for tension or compression than for longitudinal strain, even during axial fingertip loading. Blood perfusion peaked and dropped as the finger deformed during finger presses, indicating an initial dispersion and decrease of blood perfusion levels. Force sensitive resistors to force plate comparisons showed similar force curve patterns as fingers were depressed, indicating suitable functionality for future testing. Strategies for proper placement and protection of these sensors for ideal data collection and longevity through the test session were developed and will be implemented going forward for future testing

The role of deleterious passengers in cancer

The development of cancer from a population of precancerous cells is a rapid evolutionary process. During progression, cells evolve several new traits for survive and proliferation via a few key `driver' mutations. However, these few driver alterations reside in a cancer genome alongside tens of thousands of additional `passenger' mutations. Passengers are widely believed to have no role in cancer, yet many passengers fall within functional genomic elements that may have potentially deleterious effects on the cancer cells. Here we investigate the potential of moderately deleterious passengers to accumulate and alter neoplastic progression. Evolutionary simulations suggest that moderately-deleterious passengers accumulate during progression and largely evade natural selection. Accumulation is possible because of cancer's unique evolutionary constraints: an initially small population size, an elevated mutation rate, and a need to acquire several driver mutations within a short evolutionary timeframe. Cancer dynamics can be theoretically understood as a tug-of-war between rare, strongly-beneficial drives and frequent mildly-deleterious passengers. In this formalism, passengers present a barrier to cancer progression describable by a critical population size, below which most lesions fail to progress, and a critical mutation rate, above which cancers collapse. In essence, cancer progression can be subverted by its own unique evolutionary constraints. The collective burden of passengers explain several oncological phenomena that are difficult to explain otherwise. Genomics data confirms that many passengers are likely damaging and have largely evaded negative selection, while age-incidence curves and the distribution of mutation totals suggests that drivers and passengers exhibit competing effects. These data also provide estimates of the strength of drivers and passengers. Finally, we use our model to explore cancer treatments. We identify two broad regimes of adaptive evolutionary dynamics and use these regimes to understand outcomes from various treatment strategies. Our theory explains previously paradoxical treatment outcomes and suggest that passengers could serve as a biomarker of response to mutagenic therapies. Deleterious passengers are targetable by either (i) increasing the mutation rate or (ii) exacerbating their deleterious effects. Our results suggest a unique framework for understanding cancer progression as a balance between driver and passenger mutations

Oncogene-triggered suppression of DNA repair leads to DNA instability in cancer

DNA instability is an important contributor to cancer development. Previously, defects in the chromosome segregation and excessive DNA double strand breaks due to the replication or oxidative stresses were implicated in DNA instability in cancer. Here, we demonstrate that DNA instability can directly result from the oncogene-induced senescence signaling. Expression of the activated form of Her2 oncogene, NeuT, in immortalized breast epithelial cells led to downregulation of the major DNA repair factor histone H2AX and a number of other components of the HR and NHEJ double strand DNA breaks repair pathways. H2AX expression was regulated at the transcriptional level via a senescence pathway involving p21-mediated regulation of CDK and Rb1. The p21-dependent downregulation of H2AX was seen both in cell culture and the MMTV-neu mouse model of Her2-positive breast cancer. Importantly, downregulation of H2AX upon Her2/NeuT expression impaired repair of double strand DNA breaks. This impairment resulted in both increased DNA instability in the form of somatic copy number alterations, and in increased sensitivity to the chemotherapeutic drug doxorubicin. Overall, these findings indicate that the Her2/NeuT oncogene signaling directly potentiates DNA instability and increases sensitivity to DNA damaging treatments

Adaptive Identification and Control for Underwater Vehicles: Theory and Comparative Experimental Evaluations

This Thesis reports several novel algorithms for state observation, parameter identification, and control of second-order plants. A stability proof for each novel result is included. The primary contributions are adaptive algorithms for underwater vehicle (UV) plant parameter identification and model-based control. Where possible, comparative experimental evaluations of the novel UV algorithms were conducted using the Johns Hopkins University Hydrodynamic Test Facility. The UV adaptive identification (AID) algorithms reported herein estimate the plant parameters (hydrodynamic mass, quadratic drag, gravitational force, and buoyancy parameters) of second-order rigid-body UV plants under the influence of actuator forces and torques. Previous adaptive parameter identification methods have focused on model-based adaptive tracking controllers; however, these approaches are not applicable when the plant is either uncontrolled, under open-loop control, or using any control law other than a specific adaptive tracking controller. The UV AID algorithms reported herein do not require simultaneous reference trajectory-tracking control, nor do they require instrumentation of linear acceleration or angular acceleration. Thus, these results are applicable in the commonly occurring cases of uncontrolled vehicles, vehicles under open-loop control, vehicles using control methods prescribed to meet other application-specific considerations, and vehicles not instrumented to measure angular acceleration. In comparative experimental evaluations, adaptively identified plant models (AIDPMs) were shown to accurately model experimentally measured UV performance. The UV model-based control (MBC) and adaptive model-based control (AMBC) algorithms reported herein provide asymptotically exact trajectory-tracking for fully coupled second-order rigid-body UV plants. In addition, the AMBC algorithm estimates the plant parameters (hydrodynamic mass, quadratic drag, gravitational force, and buoyancy parameters) for this class of plants. A two-step AMBC algorithm is also reported which first identifies gravitational plant parameters to be used in a separate AMBC algorithm for trajectory-tracking. We report a comparative experimental analysis of proportional derivative control (PDC) and AMBC during simultaneous motion in all degrees-of-freedom. This analysis shows AMBC (i.e. simultaneous adaptation of all plant parameter estimates) can be unstable in the presence of unmodeled thruster dynamics; two-step AMBC is robust to the presence of unmodeled thruster dynamics; and two-step AMBC provides 30% better position tracking performance and 8% worse velocity tracking performance over PDC. To the best of our knowledge, the reported comparative experimental evaluation of AMBC and PDC is the first to consider trajectory-tracking performance during simultaneous motion in all degrees-of-freedom

The Potential of Wearable Sensor Technology for EVA Glove Ergonomic Evaluation

Injuries to the hands are common among astronauts who train for extravehicular activity (EVA). Many of these injuries refer to the gloves worn during EVA as the root cause. While pressurized, the bladder and outer material of these gloves restrict movement and create pressure points while performing tasks, sometimes resulting in pain, muscle fatigue, abrasions, and occasionally a more severe injury, onycholysis (fingernail delamination). The most common injury causes are glove contact (pressure point/rubbing), ill-fitting gloves, and/or performing EVA tasks in pressurized gloves. A brief review of the Lifetime Surveillance of Astronaut Health's injury database reveals over 57% of the total injuries to the upper extremities during EVA training occurred either to the metacarpophalangeal (MCP) joint, fingernail, or the fingertip. Twenty-five of these injuries resulted in a diagnosis of onycholysi