Mechanistic and Statistical Models to Understand CXCL12/CXCR4/CXCR7 in Breast Cancer.

Signaling via the CXCL12/CXCR4 axis is instrumental to the metastasis of more than 20 cancers, yet blocking the pathway alone has not been effective as cancer therapy. Since cancer progression results from a complex network of interdependent biological events, preventing metastasis cannot be understood by studying only one gene or protein at a time. In this thesis, we employed mathematical and statistical models to examine complexity in the CXCL12/CXCR4/CXCR7 signaling axis. First, we performed a comprehensive analysis of CXCL12 isoform expression in breast cancer. This is the first study to correlate the expression levels of all six CXCL12 isoforms to cancer survival outcomes. Second, to understand mechanisms of physiological gradient formation, we built a hybrid agent-based model of cancer cell chemotaxis that links molecular scale events to chemokine gradient shaping and sensing. Third, to understand how co-expression of CXCR7 may alter CXCR4 signaling, we constructed a mechanistic model of CXCR4/CXCR7 receptor dynamics and signaling with an emphasis on shared signaling components. Themes arising from this work include the importance of non-specific binding of ligand to surfaces, receptor desensitization, gradient sensing, and compensatory effects resulting from the competition of shared signaling components.PhDChemical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/111458/1/seiwon_1.pd

Coordinated semi-adaptive closed-loop control for infusion of two interacting medications

This paper presents a coordinated and semi‐adaptive closed‐loop control approach to the infusion of 2 interacting medications. The proposed approach consists of an upper‐level coordination controller and a lower‐level semi‐adaptive controller. The coordination controller recursively adjusts the reference targets based on the estimated dose‐response relationship of a patient to ensure that they can be achieved by the patient. The semi‐adaptive controller drives the patient outputs to the reference targets while estimating the patient's dose‐response relationship online. In this way, the controller is resilient to unachievable caregiver‐specified reference targets and responsive to the medication needs of individual patients. To establish the proposed approach, we developed the following: (1) a linear two‐input–two‐output dose‐response model; (2) a two‐input–two‐output semi‐adaptive controller to regulate the patient outputs while adapting high‐sensitivity parameters in the patient model; and (3) a coordination controller to adjust the reference targets that reconcile caregiver inputs and medication use. The proposed approach was applied to an example scenario in which cardiac output and respiratory rate are regulated via infusion of propofol and remifentanil in an in silico simulation setting. The results show that the coordinated semi‐adaptive control could (1) track achievable reference targets with consistent transient and steady‐state performance and (2) resiliently adjust the unachievable reference targets to achievable ones

MagNeed - Needle-Shaped Electromagnets for Localized Actuation Within Compact Workspaces

Electromagnetic actuation of micro-/milli-sized agents has traditionally relied on large electromagnets positioned at considerable distances from the agents. As a result, the electromagnets consume kilowatts of power to overcome the limited generation of magnetic field gradients. Miniaturized electromagnets offer an alternative approach for reducing power consumption via localized actuation of micro-/milli-sized agents. Typically, the generation of magnetic field gradients in the vicinity of a miniaturized electromagnet is comparable with traditional electromagnetic actuation systems. Miniaturized electromagnets can be positioned near target sites in microfluidic channels or ex vivo vasculatures. Thereby, localized trapping and actuation of magnetic micro-/milli-sized agents are carried out. This study introduces MagNeed - an electromagnetic actuation system composed of three needle-shaped electromagnets (NSEs). MagNeed can determine compact workspaces by positioning the NSEs at different spatial configurations. Each NSE generates magnetic field gradients (up to 3.5 T/m at 5 mm from the NSE tip axis) while keeping a maximum power consumption (0.5 W) and temperature (&lt; 42°C). MagNeed is complemented by a framework that reconstructs the pose of the NSEs. Experiments test MagNeed and framework on a transparent Teflon tube (5 mm inner diameter). MagNeed demonstrates localized trapping and actuation of a 1 mm NdFeB bead against a flow of water and silica gel particles (1-3 mm diameter).</p

Association between Workplace Risk Factor Exposure and Sleep Disturbance: Analysis of the 2nd Korean Working Conditions Survey

OBJECTIVES: Sleep is essential for human beings to live and work properly. This study was conducted to investigate the relationship between occupational exposures to workplace risk factors and sleep disturbance in Korean workers. METHODS: The data were drawn from the second Korean Working Conditions Survey (KWCS); a total of 7,112 paid workers were analyzed. The independent variables were occupational exposures such as physical, chemical, biological, and psychosocial risk factor in the workplace, and psychosocial risk factor was divided into five categories (job demand, job control, social support, job insecurity, lack of reward). We estimated the relationship between various occupational exposures and sleep disturbance using multivariate logistic regression analysis. RESULTS: The results showed that people who exposed to physical, chemical, biological, and psychosocial (high job demand, inadequate social support, lack of reward) risk factors were more likely to increase the risk of sleep disturbance. Furthermore, after adjusting for general and occupational characteristics, we found significant positive associations between exposures to physical (odds ratios [OR] 1.47, 95% confidence interval [CI] 1.05-2.07) and psychosocial (high job demand (OR 2.93, 95% CI 2.16-3.98), inadequate social support (OR 1.57, 95% CI 1.14-2.15), lack of reward (OR 1.45, 95% CI 1.08-1.96)) risk factors and sleep disturbance. CONCLUSION: These results suggest that occupational exposures to physical and psychosocial workplace risk factors are significantly related to sleep disturbance

Metabolic Super Scan in 18F-FDG PET/CT Imaging

A 50-yr-old man presented with intermittent hemoptysis and was diagnosed small cell lung cancer. 18F-FDG PET/CT for staging demonstrated extensive hypermetabolic lesions throughout the skeleton and liver. Interestingly, skeletal muscles of limbs, mediastinum, bowel, and especially brain showed very low FDG uptake. Because of some characteristics in common with super scan on skeletal scintigraphy, this case could be considered as 'metabolic super scan'

Model Independent Higgs Boson Mass Limits at LEP

We derive model-independent constraints on Higgs mass and couplings from associated signals for higher masses, accessible at LEP2. This work is motivated by the fact that, in many extensions of the standard model, the Higgs boson can have substantial "invisible" decay modes, for example, into light or massless weakly interacting Goldstone bosons associated to the spontaneous violation of lepton number below the weak scale.Comment: FTUV/93-19, 13 pag + 2 figures(not included but available upon request), Late

Closed-Loop Fluid Resuscitation Control Via Blood Volume Estimation

This paper presents a closed-loop control of fluid resuscitation to overcome hypovolemia based on model-based estimation of relative changes in blood volume (BV). In this approach, the control system consists of a model-based relative BV (RBV) estimator and a feedback controller. The former predicts relative changes in the BV response to augmented fluid by analyzing an arterial blood pressure (BP) waveform and the electrocardiogram (ECG). Then, the latter determines the amount of fluid to be augmented by comparing target versus predicted relative changes in BV. In this way, unlike many previous methods for fluid resuscitation based on controlled variable(s) nonlinearly correlated with the changes in BV, fluid resuscitation can be guided by a controlled variable linearly correlated with the changes in BV. This paper reports initial design of the closed-loop fluid resuscitation system and its in silico evaluation in a wide range of hypovolemic scenarios. The results suggest that closed-loop fluid resuscitation guided by a controlled variable linearly correlated with the changes in BV can be effective in overcoming hypovolemia: across 100 randomly produced hypovolemia cases, it resulted in the BV regulation error of 7.98 6 171.6 ml, amounting to 0.18 6 3.04% of the underlying BV. When guided by pulse pressure (PP), a classical controlled variable nonlinearly correlated with the changes in BV; the same closed-loop fluid resuscitation system resulted in persistent under-resuscitation with the BV regulation error of À779.1 6 147.4 ml, amounting to À13.9 6 2.65% of the underlying BV