Orally Available Near Infrared Imaging Agents for the Early Detection of Diseases

Early detection and treatment of diseases has the potential to dramatically improve patient outcomes. Diseases like cancer have shown remarkably higher survival rates when the cancer is detected early, before it has had a chance to metastasize and migrate to different regions. One way to increase rates of early detection is to implement annual screenings. Current screening methods often focus on blood tests, which gather molecular information from the circulation, or imaging, which provides anatomical details. Molecular imaging has the ability to provide both types of information, but the high cost and radiation risk often preclude its use in population screening. In this thesis, we hypothesized that near-infrared fluorescent imaging agents could be administered orally and yield sufficient contrast for disease diagnosis. The use of NIR fluorescent targeting ligands provides both spatial and molecular information while making the entire process fast, inexpensive, completely non-invasive, and safe with the use of non-ionizing radiation. For proof-of-concept studies to develop this novel technique, we selected integrin of the form αvβ3 as the target, and a high affinity peptidomimetic as the ligand. The major challenge of developing an orally available imaging agent is that orally available drugs are typically small in size and lipophilic in nature, while imaging agents tend to be larger in size and hydrophilic. In spite of these challenges, an IRDye800CW-labeled agent had an oral absorption of 2.3% and was selected for studies in the detection of two diseases: breast cancer and rheumatoid arthritis. Mammography uses x-rays to detect suspicious lesions when screening for breast cancer but only provides anatomical data, which has lead to high false positive rates and an estimated $4 billion in expenditure due to overdiagnosis. The IRDye800CW agent was dosed at 5 mg/kg in an orthotopic tumor xenograft mouse model. Live animal imaging at 6, 24 and 48 hours post administration showed the highest target to background ratio of ~4 at 48 hours and histology showed high uptake of the agent by macrophages and breast cancer cells. Rheumatoid arthritis (RA) is an autoimmune disease that leads to largely irreversible joint damage over time, but effective treatments are available. Therefore, there is intense interest in early detection of RA to prevent further damage, and some studies have even indicated that the disease could be cured if detected early. However, current methods lack the sensitivity to detect RA at an early stage. Oral delivery of the IRDye800CW agent in a collagen antibody induced arthritis mouse model showed significantly higher uptake in the inflamed joints compared to healthy joints. To scale the expected signal to clinically relevant depths, we developed a 3D COMSOL model for optical simulations of RA detection in the human hand. The simulations showed that for target to background concentration ratios of the imaging agent of 5.5 and 6.5, there was 95% and 98% probability of detection of the inflamed joint. The in vivo mouse model had an estimated target to background concentration ratio of ~20, which makes the detection of RA in humans very promising. This dissertation demonstrates the oral delivery of molecular imaging agents for the detection of breast cancer and RA in relevant mouse models. These studies provide the foundation to develop a range of oral molecular imaging agents for other biomarkers and diseases with the potential for earlier diagnosis to improve patient outcomes.PHDChemical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/147662/1/sumitbh_1.pd

RARE SURVIVAL AFTER SEVERE ALUMINIUM PHOSPHIDEPOISOININGAFTER MYOCARDITISWITH L-CARNITINE AND STEROID

Acute Aluminium Phosphide or Celphos poisoning is a common agrochemical fumigant used commonly in countries like South East Asia and China. It is extremely lethal poison as there is no specific antidote and involvement of multisystem organ involvement in a short span of time. Presenting a case of a patient took two tablets of Celphos and developed myocarditis with persistent hypotension due to myocarditis and ventricular tachyarrhythmia, which reverted to normal with steroid, L-carnitine and magnesium therapy, which is a rare entity to the best of our knowledge.Â

Multichannel Imaging to Quantify Four Classes of Pharmacokinetic Distribution in Tumors

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108598/1/jps24086.pd

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Search for supersymmetry in events with one lepton and multiple jets in proton-proton collisions at root s=13 TeV

Peer reviewe

Measurement of the top quark forward-backward production asymmetry and the anomalous chromoelectric and chromomagnetic moments in pp collisions at √s = 13 TeV

Abstract The parton-level top quark (t) forward-backward asymmetry and the anomalous chromoelectric (d̂ t) and chromomagnetic (μ̂ t) moments have been measured using LHC pp collisions at a center-of-mass energy of 13 TeV, collected in the CMS detector in a data sample corresponding to an integrated luminosity of 35.9 fb−1. The linearized variable AFB(1) is used to approximate the asymmetry. Candidate t t ¯ events decaying to a muon or electron and jets in final states with low and high Lorentz boosts are selected and reconstructed using a fit of the kinematic distributions of the decay products to those expected for t t ¯ final states. The values found for the parameters are AFB(1)=0.048−0.087+0.095(stat)−0.029+0.020(syst),μ̂t=−0.024−0.009+0.013(stat)−0.011+0.016(syst), and a limit is placed on the magnitude of | d̂ t| < 0.03 at 95% confidence level. [Figure not available: see fulltext.

Measurement of the top quark mass using charged particles in pp collisions at root s=8 TeV

Peer reviewe

Measurement of t(t)over-bar normalised multi-differential cross sections in pp collisions at root s=13 TeV, and simultaneous determination of the strong coupling strength, top quark pole mass, and parton distribution functions

Peer reviewe

An embedding technique to determine ττ backgrounds in proton-proton collision data

An embedding technique is presented to estimate standard model tau tau backgrounds from data with minimal simulation input. In the data, the muons are removed from reconstructed mu mu events and replaced with simulated tau leptons with the same kinematic properties. In this way, a set of hybrid events is obtained that does not rely on simulation except for the decay of the tau leptons. The challenges in describing the underlying event or the production of associated jets in the simulation are avoided. The technique described in this paper was developed for CMS. Its validation and the inherent uncertainties are also discussed. The demonstration of the performance of the technique is based on a sample of proton-proton collisions collected by CMS in 2017 at root s = 13 TeV corresponding to an integrated luminosity of 41.5 fb(-1).Peer reviewe