Improving the delivery and efficacy of a cancer therapeutic via extracellular matrix modification

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, February 2008.Includes bibliographical references.The extracellular matrix (ECM) has been shown to be a significant source of hindrance to the transport of macromolecules in solid tumors. This thesis shows that by limiting their interstitial transport, the tumor ECM can reduce the efficacy of cancer therapeutics. Furthermore, techniques for overcoming this transport barrier and improving the effectiveness of existing cancer therapetuics are developed. Mathematical modeling was utilized to characterize the distribution of a therapeutic herpes simplex virus (HSV) vector in solid tumors. The model showed that the spread of virus following intratumoral injection is severely limited by rapid binding and limited diffusion. Importantly, the model demonstrates that an improvement in virus diffusion can enhance its distribution significantly. In vivo multiphoton imaging of fibrillar collagen type I and injected HSV vectors largely supported the model predictions. Injected viral particles could not penetrate dense networks of fibrillar collagen. Both the initial distribution and subsequent propagation of these replication-competent vectors were limited by collagen. Degradation of tumor collagen with bacterial collagenase enhanced the distribution and efficacy of the virus. To develop a technique that is clinically applicable, human collagenases were screened for similar activity. Matrix metalloproteinase (MMP) -1 and -8 were identified as viable candidates and tested for their ability to degrade collagen and enhance diffusion in tumors. When overexpressed in tumors, neither MMP significantly altered collagen content or diffusive transport. However, these MMPs have multiple matrix substrates and were found to deplete the tumor of sulfated glycosaminoglycans (GAGs). This, in turn, increased the hydraulic conductivity of these tumors, enhancing the distribution and efficacy of infused oncolytic HSV. Genetic mutations were employed to enhance the activity of these enzymes, but impaired intracellular processing and inactivating autoproteolytic degradation reduced overall activity.(cont.) Thus, our work demonstrates the importance of the tumor extracellular matrix in regulating the distribution and efficacy of cancer therapeutics. Methods to modulate both tumor collagen and sulfated GAGs are developed to enhance interstitial transport and improve the treatment of solid tumors.by Wilson Mok.Ph.D

Integration of Learning, Situational Power and Goal Constraints Into Time-Dependent Electronic Negotiation Agents

In the past decade, electronic negotiation has become an important research topic in the field of information systems. A desirable goal of negotiation agents is to understand their owners' requirements, and to learn their opponents' behavior, thereby lessening the involvement of human beings. Studies on human negotiation bring out that several issues can affect a human's negotiation behavior, including learning an opponent's behavior, exerting power on an opponent, and setting an individual goal to improve the level of accomplishment. Research on incorporating these issues into negotiation agents is, however, still at an infancy state. We therefore take up this topic in this thesis. Researchers have proposed many different negotiation agents that follow a preset behavior based on human models of negotiation. In this thesis, we consider one such model, known as the time-dependent-tactical model, which is used by human negotiators and in which the values of the negotiating issues are determined based on the time elapsed in the negotiation. A learning mechanism for this model might be beneficial, because this model is frequently used in electronic negotiation. Thus, we propose heuristic algorithms that estimate the parameters of an agent's time-dependent-tactical model, and that then react to the estimated parameters for achieving higher negotiation performance. Besides learning, we incorporate two other factors that have been found to affect a human negotiation outcome. These are situational power, which represents differences in negotiators' status based on market conditions, and goal constraints, which stand for the levels of accomplishment negotiators try to strive for. To validate the impacts of learning, situational power and goal constraints in electronic negotiation, we first present how to integrate these features into negotiation agents, and then conduct simulations. With 187,500 simulation runs, we observe that our learning algorithms are effective in improving both individual and dyadic negotiation performances. For the effects of situational power and goal constraints, we obtain congruent results between human and electronic negotiations. By incorporating learning into situational power and goal constraints, we achieve significant joint effect between learning and situational power as well as that between learning and goal constraints. In summary, this thesis provides three primary contributions to the fields of information systems and electronic-commerce research. First, we have designed algorithms for learning an opponent's negotiation behavior. Second, our learning algorithms are found to be effective in improving negotiation performance. Third, we have shown how learning can be integrated with situational power and goal constraints, although this is not a major focus in this study. Finally, the agreement on the joint effects of learning, situational power and goal constraints between human and electronic negotiations suggests that our integrated design of the agent appears to be effective

The JCMT Nearby Galaxies Legacy Survey -- XI. -- Environmental Variations in the Atomic and Molecular Gas Radial Profiles of Nearby Spiral Galaxies

This article has been accepted for publication in Monthly Notices of the Royal Astronomical Society. ©: 2017 The Author (s). Published by Oxford University Press on behalf of the Royal Astronomical Society. All rights reserved.We present an analysis of the radial profiles of a sample of 43 HI-flux selected spiral galaxies from the Nearby Galaxies Legacy Survey (NGLS) with resolved James Clerk Maxwell Telescope (JCMT) CO $J=3-2$ and/or Very Large Array (VLA) HI maps. Comparing the Virgo and non-Virgo populations, we confirm that the HI disks are truncated in the Virgo sample, even for these relatively HI-rich galaxies. On the other hand, the H$_{2}$ distribution is enhanced for Virgo galaxies near their centres, resulting in higher H$_{2}$ to HI ratios and steeper H$_{2}$ and total gas radial profiles. This is likely due to the effects of moderate ram pressure stripping in the cluster environment, which would preferentially remove low density gas in the outskirts while enhancing higher density gas near the centre. Combined with H$\alpha$ star formation rate data, we find that the star formation efficiency (SFR/H$_{2}$) is relatively constant with radius for both samples, but Virgo galaxies have a $\sim40\%$ lower star formation efficiency than non-Virgo galaxies.Peer reviewedFinal Published versio

The JCMT Nearby Galaxies Legacy Survey – XI. Environmental Variations in the Atomic and Molecular Gas Radial Profiles of Nearby Galaxies

We present an analysis of the radial profiles of a sample of 43 H I-flux selected spiral galaxies from the Nearby Galaxies Legacy Survey (NGLS) with resolved James Clerk Maxwell Telescope (JCMT) CO J = 3 − 2 and/or Very Large Array (VLA) H I maps. Comparing the Virgo and non-Virgo populations, we confirm that the H i discs are truncated in the Virgo sample, even for these relatively H i-rich galaxies. On the other hand, the H2 distribution is enhanced for the Virgo galaxies near their centres, resulting in higher H2 to H I ratios and steeper H2 and total gas radial profiles. This is likely due to the effects of moderate ram pressure stripping in the cluster environment, which would preferentially remove low-density gas in the outskirts while enhancing higher density gas near the centre. Combined with Hα star formation rate data, we find that the star formation efficiency (SFR/H2) is relatively constant with radius for both samples, but the Virgo galaxies have an ∼40 per cent lower star formation efficiency than the non-Virgo galaxies

Lista atualizada de quirópteros da Amazônia Brasileira

We present an updated checklist on bats of the Amazon Basin in Brazil, based on our collection of 3.081 specimens in 12 areas in the Basin and a review of the existing literature. The list consists of 95 species belonging to 51 genera and 9 families: 3 species (Micronycteris hirsuta, Natalus stramineus and Rhogessa tumida) are being cited for the first time as present in the Amazon Basin; of the remaining 92 species reported by previous workers. 68 were registered and confirmed by the present authors.É apresentada uma lista atualizada de quirópteros da região amazônica brasileira, baseada em nossa coleção de 3.081 exemplares capturados em 12 áreas na Bacia Amazônica e com referência às literaturas anteriormente publicadas. A lista conta com 95 espécies de 51 gêneros e 9 famílias, sendo 3 espécies (Micronycteris hirsuta, Natalus stramineus e Rhogessa tumida) citadas pela primeira vez como ocorrendo na região; e das demais alistadas por pesquisadores anteriores, são registradas e confirmadas 68 espécies

The Effect of Galaxy Interactions on Molecular Gas Properties

© 2018. The American Astronomical Society. All rights reserved.Galaxy interactions are often accompanied by an enhanced star formation rate (SFR). Since molecular gas is essential for star formation, it is vital to establish whether and by how much galaxy interactions affect the molecular gas properties. We investigate the effect of interactions on global molecular gas properties by studying a sample of 58 galaxies in pairs and 154 control galaxies. Molecular gas properties are determined from observations with the JCMT, PMO, and CSO telescopes and supplemented with data from the xCOLD GASS and JINGLE surveys at 12CO(1-0) and 12CO(2-1). The SFR, gas mass (), and gas fraction (f gas) are all enhanced in galaxies in pairs by ∼2.5 times compared to the controls matched in redshift, mass, and effective radius, while the enhancement of star formation efficiency (SFE ≡SFR/) is less than a factor of 2. We also find that the enhancements in SFR, and f gas, increase with decreasing pair separation and are larger in systems with smaller stellar mass ratio. Conversely, the SFE is only enhanced in close pairs (separation <20 kpc) and equal-mass systems; therefore, most galaxies in pairs lie in the same parameter space on the SFR- plane as controls. This is the first time that the dependence of molecular gas properties on merger configurations is probed statistically with a relatively large sample and a carefully selected control sample for individual galaxies. We conclude that galaxy interactions do modify the molecular gas properties, although the strength of the effect is dependent on merger configuration.Peer reviewedFinal Accepted Versio

Influence of production variables and starting material on charcoal stable isotopic and molecular characteristics

We present a systematic study on the effect of starting species, gas composition, temperature, particle size and duration of heating upon the molecular and stable isotope composition of high density (mangrove) and low density (pine) wood. In both pine and mangrove, charcoal was depleted in o13C relative to the starting wood by up to 1.6&#37; and 0.8&#37;, respectively. This is attributed predominantly to the progressive loss of isotopically heavier polysaccharides, and kinetic effects of aromatization during heating. However, the pattern of o13C change was dependant upon both starting species and atmosphere, with different structural changes associated with charcoal production from each wood type elucidated by Solid-State o13C Nuclear Magnetic Resonance Spectroscopy. These are particularly evident at lower temperatures, where variation in the oxygen content of the production atmosphere results in differences in the thermal degradation of cellulose and lignin. It is concluded that production of charcoal from separate species in identical conditions, or from a single sample exposed to different production variables, can result in significantly different o13C of the resulting material, relative to the initial wood. These results have implications for the use of charcoal isotope composition to infer past environmental change

Bronchiectasis in yellow nail syndrome

BACKGROUND AND OBJECTIVE: Yellow nail syndrome (YNS) is a rare and poorly described disease process. In this case-control study, clinical features and findings on HRCT were compared with idiopathic bronchiectasis (IBx). METHODS: A review of all patients attending an adult bronchiectasis clinic between 2007 and 2013 identified 25 YNS patients. IBx patients were matched in a 2:1 ratio for age, duration of symptoms and gender. RESULTS: Median age of onset was 53 years. There were 12 male and 23 Caucasian YNS patients. Respiratory manifestations included chronic productive cough (100%), chronic rhinosinusitis (88%), pleural effusions (20%) and lymphoedema (12%). Chest symptoms preceded yellow nails in the majority (68%). Abnormal nails persisted at follow-up in 23 of 25 patients but improved in 14. In both disorders, there was symmetrical, predominantly lower lobe bronchiectasis on HRCT. Extent (P = 0.04), severity (P = 0.03) and bronchial wall thickness (P = 0.05) scores were lower in YNS, with less upper and middle lobe disease. Multivariate analysis showed an independent association with increased mucus plugging in YNS. There was a similar prevalence of Pseudomonas aeruginosa infection and mild lung function abnormalities. CONCLUSION: Bronchiectasis in YNS is less severe than IBx but is associated with increased mucus plugging, onset is in middle age and there is no female predominance. Treatment targeted at improved secretion clearance may improve both chest and nail symptoms, with consideration of long-term macrolide antibiotics