Exploring the mutagenic consequences of inflammation and DNA damage

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biological Engineering, 2018.Cataloged from PDF version of thesis.Includes bibliographical references.Inflammation is a major risk factor for many types of cancer, and the physiological processes involved in inflammation can contribute to many aspects of cancer development. Inflammation entails reprogramming of cell behaviors that resemble cancer, such as increased proliferation and signals for survival and migration, and it also entails production of reactive chemical species, which can damage DNA to promote genetic instability, another hallmark of cancer. While much research has been dedicated to studying the relationships between inflammation and cancer, it has been difficult to distinguish the relative contributions of modified cell behavior and de novo mutagenesis to the development of cancer. Furthermore, few studies have addressed the role(s) inflammation plays in cancer initiation versus promotion. Here, we utilized a transgenic mouse for detecting mutations in a variety of models of inflammation to parse the mechanisms by which inflammation contributes to mutations and cancer. The RaDR mouse, developed in the Engelward lab, contains a ubiquitously expressed transgene that enables detection of sequence rearrangement mutations following aberrant homologous recombination (HR). These mice also contain the Gpt-[delta] transgene for detecting point mutations and deletions, enabling unprecedented breadth and depth of possible mutation analyses in a single tissue. Our studies began by querying whether elements that regulate inflammation protect against mutagenesis in RaDR animals. We then studied RaDR mutagenesis in several models of intestinal inflammation and cancer. Together, these experiments showed that inflammation does not significantly induce de novo sequence rearrangement mutations, but it greatly increases the overall burden of mutant cells in a tissue as a result of heightened proliferation and clonal expansion. We also used the RaDR mouse model to expand upon studies of DNA repair pathway balance. DNA damage is addressed by a network of pathways, each designed to identify and repair specific types of lesions. One of the most important repair pathways for DNA damage caused by inflammation is the Base Excision Repair (BER) pathway, and we have previously found that BER intermediates can increase the frequency of mutagenic HR. Here, we expand upon that information, showing that acceleration of the BER pathway by increased expression of an initiating enzyme does not increase sequence rearrangement mutations, provided the downstream pathway can be resolved efficiently. Together, the studies described herein demonstrate that inflammation is unlikely to initiate cancer via sequence rearrangement mutations, but inflammation is a strong promoter of cancer in part through increased clonal expansion of mutant cells.by Jennifer Elizabeth Kay.Ph. D

Bremsstrahlung in the gravitational field of a cosmic string

In the framework of QED we investigate the bremsstrahlung process for an electron passing by a straight static cosmic string. This process is precluded in empty Minkowski space-time by energy and momentum conservation laws. It happens in the presence of the cosmic string as a consequence of the conical structure of space, in spite of the flatness of the metric. The cross section and emitted electromagnetic energy are computed and analytic expressions are found for different energies of the incoming electron. The energy interval is divided in three parts depending on whether the energy is just above electron rest mass $M$, much larger than $M$, or exceeds $M/\delta$, with $\delta$ the string mass per unit length in Planck units. We compare our results with those of scalar QED and classical electrodynamics and also with conic pair production process computed earlier.Comment: 21 pages, to appear in Phys. Rev. D., KONS-RGKU-94-0

Executive function does not predict coping with symptoms in stable patients with a diagnosis of schizophrenia

<p>Abstract</p> <p>Background</p> <p>Associations between coping with and control over psychotic symptoms were examined using the Maastricht Assessment of Coping Strategies-24, testing the hypothesis that the cognitive domain of executive functioning predicted quality and quantity of coping.</p> <p>Methods</p> <p>MACS-24 was administered to 32 individuals with a diagnosis of schizophrenia. For each of 24 symptoms, experience of distress, type of coping and the resulting degree of perceived control were assessed. Coping types were reduced to two contrasting coping categories: symptomatic coping (SC) and non-symptomatic coping (NSC; combining active problem solving, passive illness behaviour, active problem avoiding, and passive problem avoiding). Cognitive functioning was assessed using the GIT (Groninger Intelligence Test), the Zoo map (BADS: Behavioural Assessment of Dysexecutive function), Stroop-test and Trail making.</p> <p>Results</p> <p>Cognitive function was not associated with frequency of coping, nor did cognitive function differentially predict SC or NSC. Cognitive function similarly was not associated with symptom distress or level of perceived control over the symptom.</p> <p>Conclusion</p> <p>There was no evidence that cognitive function predicts quantity or quality of coping with symptoms in people with a diagnosis of schizophrenia. Variation in the realm of emotion regulation and social cognition may be more predictive of coping with psychotic symptoms.</p

Metacognitive Reflection and Insight Therapy (MERIT) with a Patient with Persistent Negative Symptoms

Metacognition comprises a spectrum of mental activities involving thinking about thinking. Metacognitive impairments may sustain and trigger negative symptoms in people with schizophrenia. Without complex ideas of the self and others, there may be less reason to pursue goal-directed activities and less ability to construct meaning in daily activities, leading to the experience of negative symptoms. As these symptoms tend to be nonresponsive to pharmacotherapy and other kinds of treatment metacognition might be a novel treatment target; improvement of metacognition might lead to improvements in negative symptoms. One therapy that seeks to promote metacognition is the Metacognitive Reflection and Insight Therapy (MERIT). In this study, a case is presented in which a first episode patient with severe negative symptoms is treated with MERIT. A case illustration and the eight core principles of MERIT are presented. Independent assessments of metacognition and negative symptoms before and after therapy show a significant increase of metacognition and decrease of negative symptoms over the course of 40 weeks

Glycan composition of serum alpha-fetoprotein in patients with hepatocellular carcinoma and non-seminomatous germ cell tumour

Although estimation of serum alpha-fetoprotein (AFP) is widely used in the diagnosis of hepatocellular carcinoma (HCC) and non-seminomatous germ cell tumours (NSGCT), the clinical usefulness of this test is limited by a low specificity. However, there exist glycoforms of AFP which may be more specific for particular tumours. Previously, detailed analysis has been prevented by the low levels of AFP in human serum. We report here the application of fluorescence labelling, sequential exoglycosidase digestion, high-performance liquid chromatography and matrix-assisted laser desorption ionization in time-of-flight mass spectrometry, to determine the glycan structures of purified serum AFP from patients with HCC and NSGCT. Eleven major glycans were found, of which seven were N-linked, and four were O-linked, to the protein backbone. The structure of the N-linked glycans (all of bi-antennary complex-type with varying degrees of sialylation, fucosylation and galactosylation) were consistent with those previously reported. The O-linked glycans (three mucin O-GalNAc type glycans with variable degrees of sialylation, one O-HexNAc monosaccharide glycan) have not previously been reported. The finding of mucin O-GalNAc type glycans was supported by the prediction of potential O-GalNAc glycosylation sites on the protein backbone by analysis of the AFP structure by molecular modelling. With knowledge of these structures it may be possible to develop more specific assays for the detection of HCC and NSGCT. © 1999 Cancer Research Campaign © 1999 Cancer Research Campaig

Crises and collective socio-economic phenomena: simple models and challenges

Financial and economic history is strewn with bubbles and crashes, booms and busts, crises and upheavals of all sorts. Understanding the origin of these events is arguably one of the most important problems in economic theory. In this paper, we review recent efforts to include heterogeneities and interactions in models of decision. We argue that the Random Field Ising model (RFIM) indeed provides a unifying framework to account for many collective socio-economic phenomena that lead to sudden ruptures and crises. We discuss different models that can capture potentially destabilising self-referential feedback loops, induced either by herding, i.e. reference to peers, or trending, i.e. reference to the past, and account for some of the phenomenology missing in the standard models. We discuss some empirically testable predictions of these models, for example robust signatures of RFIM-like herding effects, or the logarithmic decay of spatial correlations of voting patterns. One of the most striking result, inspired by statistical physics methods, is that Adam Smith's invisible hand can badly fail at solving simple coordination problems. We also insist on the issue of time-scales, that can be extremely long in some cases, and prevent socially optimal equilibria to be reached. As a theoretical challenge, the study of so-called "detailed-balance" violating decision rules is needed to decide whether conclusions based on current models (that all assume detailed-balance) are indeed robust and generic.Comment: Review paper accepted for a special issue of J Stat Phys; several minor improvements along reviewers' comment

Search for charginos in e+e- interactions at sqrt(s) = 189 GeV

An update of the searches for charginos and gravitinos is presented, based on a data sample corresponding to the 158 pb^{-1} recorded by the DELPHI detector in 1998, at a centre-of-mass energy of 189 GeV. No evidence for a signal was found. The lower mass limits are 4-5 GeV/c^2 higher than those obtained at a centre-of-mass energy of 183 GeV. The (\mu,M_2) MSSM domain excluded by combining the chargino searches with neutralino searches at the Z resonance implies a limit on the mass of the lightest neutralino which, for a heavy sneutrino, is constrained to be above 31.0 GeV/c^2 for tan(beta) \geq 1.Comment: 22 pages, 8 figure

Hadronization properties of b quarks compared to light quarks in e+e- -> q qbar from 183 to 200 GeV

The DELPHI detector at LEP has collected 54 pb^{-1} of data at a centre-of-mass energy around 183 GeV during 1997, 158 pb^{-1} around 189 GeV during 1998, and 187 pb^{-1} between 192 and 200 GeV during 1999. These data were used to measure the average charged particle multiplicity in e+e- -> b bbar events, _{bb}, and the difference delta_{bl} between _{bb} and the multiplicity, _{ll}, in generic light quark (u,d,s) events: delta_{bl}(183 GeV) = 4.55 +/- 1.31 (stat) +/- 0.73 (syst) delta_{bl}(189 GeV) = 4.43 +/- 0.85 (stat) +/- 0.61 (syst) delta_{bl}(200 GeV) = 3.39 +/- 0.89 (stat) +/- 1.01 (syst). This result is consistent with QCD predictions, while it is inconsistent with calculations assuming that the multiplicity accompanying the decay of a heavy quark is independent of the mass of the quark itself.Comment: 13 pages, 2 figure

Quality of sleep in patients with schizophrenia is associated with quality of life and coping

BACKGROUND: While sleep disturbance is widespread in schizophrenia it is less clear whether sleep disturbance is uniquely related to impaired coping and perceived quality of life. METHODS: We simultaneously assessed sleep quality, symptoms, and coping in 29 persons with schizophrenia or schizoaffective disorder in a post acute phase of illness. Assessment instruments included the Pittsburgh Sleep Quality Index; the Positive and Negative Symptom Scale; the Heinrichs Quality of Life Scale; and the Ways of Coping Scale. Multiple regressions were performed predicting quality of life and coping from sleep quality controlling for age and symptom severity. On a subset of seven subjects non-dominant wrist actigraphy was used as an objective check of their self-reported poor sleep. RESULTS: Analyses revealed that poor sleep quality predicted low quality of life (r = -0.493; p = .022) and reduced preference for employing positive reappraisal when facing a stressor (r = -0.0594; p = 0.0012). Actigraphy confirmed poor sleep quality in a subset of subjects. They had shorter sleep duration (p < .0005), shorter average sleep episodes (p < .005) and more episodes of long awakening (p < 0.05) than community norms. CONCLUSION: The results are consistent with the hypotheses that poor sleep may play a unique role in sustaining poor quality of life and impaired coping in patients with schizophrenia. These associations may hold for community controls as well

Self-esteem is associated with premorbid adjustment and positive psychotic symptoms in early psychosis

<p>Abstract</p> <p>Background</p> <p>Low levels of self-esteem have been implicated as both a cause and a consequence of severe mental disorders. The main aims of the study were to examine whether premorbid adjustment has an impact on the subject's self-esteem, and whether lowered self-esteem contributes to the development of delusions and hallucinations.</p> <p>Method</p> <p>A total of 113 patients from the Thematically Organized Psychosis research study (TOP) were included at first treatment. The Positive and Negative Syndrome Scale (PANSS) was used to assess present symptoms. Premorbid adjustment was measured with the Premorbid Adjustment Scale (PAS) and self-esteem by the Rosenberg Self-Esteem Scale (RSES).</p> <p>Results</p> <p>Premorbid social adjustment was significantly related to lower self-esteem and explained a significant proportion of the variance in self-esteem. Self-esteem was significantly associated with the levels of persecutory delusions and hallucinations experienced by the patient and explained a significant proportion of the variance even after adjusting for premorbid functioning and depression.</p> <p>Conclusion</p> <p>There are reasons to suspect that premorbid functioning is an important aspect in the development of self- esteem, and, furthermore, that self-esteem is associated with the development of delusions and hallucinations.</p