Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2009. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Includes bibliographical references (p. 62-68). / Fifteen years ago lin-4 was reported to be the first endogenous small non-coding, but interfering RNA structure involved in developmental timing in C. elegans. First thought not, or only rarely, to occur in mammals, microRNAs are now among the major players in up-to-date genomic research. The mature molecules are ~22 nucleotides in length and, by targeting predominantly the 3' UTR of mRNAs, lead to translational repression or degradation of the target message, hence controlling important cellular mechanisms, including division, differentiation and death. This key role makes them excellent targets for cancer research. In fact they have been shown to have a major impact on cancer development in many cases. However, miRNAs are not a homogeneous class and can be sub classified into intragenic and intergenic, depending on their genomic position. Whereas intergenic miRNAs are expected to be independent transcriptional units, intragenic miRNAs are commonly believed to be regulated through their host gene. Despite of the growing knowledge on how miRNAs integrate into cellular regulatory networks, our current knowledge about the specific role of intragenic miRNAs is rather limited. In this work we integrated current miRNA knowledge bases, ranging from miRNA sequence and genomic localization information to target prediction, with biochemical pathway information and publicly available expression data to investigate functional properties of intragenic miRNAs and their relationship to their host genes. To the best of our knowledge, we are the first to show in a large-scale analysis that intragenic miRNAs seem to act as negative feedback regulators on multiple levels. We furthermore investigated the impact of this model on the potential role of intronic miRNAs in cancer pathogenesis. / by Ludwig Christian Giuseppe Hinske. / S.M.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2011. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 59-61). / Innovation within the medical device industry had led to tremendous advances in the provision of care for patients worldwide. Continued progress in the treatment of disease will require effective processes for managing and analyzing innovation within this industry. Popular models of innovation exist for many industries outside of the medical realm; however, an extensive literature search uncovered a limited body of work related to innovation within the medical device industry. Specifically, literature that examines the application of the principles of disruptive innovation to the medical device industry is limited in scope and in quantity. It is theorized that the medical device industry may have unique characteristics for disruptive innovation due to the unique economic and regulatory structures that exist within this industry. This thesis applies the principles of disruptive innovation that were popularized by Clayton Christenson's seminal work, "The Innovator's Dilemma", to the medical device industry. These characteristics are subsequently delineated and evaluated through examination of the prosthetic cardiac valve industry. This industry serves as an effective case study due to the long history of innovation and the emergence of new disruptive technology within this specialty. The categorization of a "disruptive" innovation was made when a given technology altered the value proposition for treating a disease, relative to incumbent technology. This case study was evaluated along metrics of performance characteristics, the perception of leading customers, the ability to prospectively analyze markets, and the profitability of disruptive innovation for the incumbent firm. Conclusions were reached based on an examination of relevant literature and primary research conducted with thought leaders in this area. This research supports the conclusion that the cardiac valve industry has experienced unique characteristics in the development and commercialization of disruptive innovations. Specifically, incentives appear to exist within this industry that support development and commercialization of disruptive innovations by industry incumbents. Furthermore, the importance of understanding what value proposition is being disrupted is paramount in effectively understanding the incentives of manufacturers to innovate. When a technology is developed that is disruptive to a procedure, then the manufacturer tends to behave similar to a "newentrant" within the Christenson framework. This appears to also be true when the innovation is disruptive to that manufacturer's legacy products. Additional research is warranted in extrapolating this finding to the broader medical device industry. / by David B. Berlin. / S.M.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, September 2003. / "August 2003." / Includes bibliographical references (p. 54-57). / For Parkinson's patients to function at their best, their medications need to be optimally adjusted to the diurnal variation of symptoms. For this to occur, it is important for the managing clinician to have an accurate picture of how the patient's bradykinesia/hypokinesia and dyskinesia fluctuate throughout the normal daily activities. This thesis proposes the use of wearable accelerometers coupled with machine learning and statistical techniques in order to classify the movement states of Parkinson's patients and to provide a timeline of how the patients fluctuate throughout the day. A pilot study was performed using 2 patients with the goal of assessing the ability to classify dyskinesia and bradykinesia/hypokinesia based on accelerometric data. The patients were observed and videotaped. Clinical observations of bradykinesia/hypokinesia and dyskinesia were noted every minute. Neural networks were able to classify better than classification trees with an average c-index (equivalent to the area under the ROC curve) of 0.905 for bradykinesia/hypokinesia and 0.926 for dyskinesia. A separate group of 5 patients were observed with the additional goal of building models that can classify the movement of a patient without requiring clinically annotated training data for the same patient. An enhanced protocol was used in the final study. Dichotomized linear regression was found to classify well with an average c-index of 0.8219 for body bradykinesia/hypokinesia and 0.8799 using as the gold-standard the patient's diary. Dyskinesia was classified at a c-index of 0.7522. Neural networks did not perform as well, possibly because of restrictions placed on adjusting parameters. The two most clinically important problems: predicting / (cont.) when the patient feels he/she is "off' or when he/she has "troublesome dyskinesia" were discriminated with c-indices of 0.96 and 1.0 respectively. The good result of the models despite the small number of patients is promising. Further studies with larger number of patients are therefore justified. / by David A. Klapper. / S.M.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2009. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 69-73). / Personalized medicine is the science and practice of customizing medical screening and treatment plans for an individual based on his or her genomic profile. Breast cancer is one of the first disease areas to serve as an example of this approach, where most patients have experienced its benefits through the use of genetic tests that provide decision support for health care workers regarding the likely effectiveness of specific drugs and, more broadly, the urgency of particular treatment options (for example, chemoprevention versus prophylactic surgery). Little is known about the diffusion of such personalized approaches to medical practice, particularly the factors shaping the adoption of genetic tests. While numerous medical diffusion studies have been published over the past few decades, most were univariate analyses and did not consider the unique aspects of genetic testing versus drugs. Moreover, they mainly focused on the characteristics and behaviors of physicians, patients, product manufacturers, and social networks, and did not explore the role of potentially important third parties like professional medical societies and patient groups (e.g. disease foundations and patient advocacy organizations). The aim of this thesis was to analyze the relationship between seven attributes of four breast cancer genetic tests and clinical adoption to show that standard diffusion frameworks can be enhanced through previously unstudied dimensions when evaluating personalized medicine-related innovations. / (cont.) We identified four variables that correlated with clinical adoption: 1) regulatory status, 2) inclusion in practice guidelines by professional societies, 3) explicit endorsement by patient groups, and 4) implicit endorsement by patient groups. Our findings indicate that a key overlooked element in the current literature (and potentially overlooked by the firms creating these tests) is the role of patient groups in the diffusion of novel genetic tests, in addition to endorsement from medical professional societies. These findings may add value to strategic decisions made by company executives, investors, payers, health care providers, and patients as they are presented with novel products and development opportunities in the era of personalized medicine. / by Julie Keunhee Yoo. / S.M.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2007. / Includes bibliographical references (leaves 83-85). / The pipeline productivity challenge facing large, publicly traded pharmaceutical companies, collectively referred to as "Big Pharma," is well known. The unprecedented success Big Pharma achieved over the past few decades in commercializing blockbuster products means that it is now faced with near-term patent expirations on such products, representing billions of dollars in lost sales and profits. In order to maintain its economic momentum, Big Pharma is increasingly relying on the universe of smaller, early stage biotechnology and pharmaceutical companies as a source of new products. Early stage companies may offer Big Pharma something beyond simply more product bets. Several recent consulting studies have shown that economic returns to Big Pharma of products sourced externally are greater than those developed internally, which raises the question: What, if anything, are early stage companies doing differently from Big Pharma in their product development programs? The goal of this thesis is to evaluate product development programs ("projects") and compare qualitatively and quantitatively the decisions for projects at key decision points between early stage pharmaceutical and biotechnology companies and Big Pharma. Given that much of the critical discovery and R&D work on pharmaceutical products happens both before and during a product's entry into human clinical trials, this thesis focuses on those areas of the development continuum where R&D plays a central role. The key decision points are therefore: lead candidate selection/optimization, moving a project from pre-clinical trials into Phase I human clinical trials, and moving a project from Phase I to Phase II clinical trials in humans. / (cont.) The thesis tests the hypothesis that small, early stage, publicly traded U.S. & Canadian biotech and pharma firms (Small Pharma) focused on 1-2 therapeutic areas who high levels of homogeneity in their decision making process, number of decision inputs, prioritization processes, and metrics for all three key decision points in the product development process irrespective of whether a product originates inside or outside the company. In comparison, Big Pharma companies will show heterogeneity in these variables for their projects. I have obtained data from primary interviews of industry executives within Big Pharma and Small Pharma firms. The therapeutic areas selected for the early stage company data set are: (1) cancer and autoimmune disease, (2) cardiovascular disease, and (3) infectious disease. The rationale for these therapeutic areas is that there is significant drug development activity taking place in these fields, and there are significant unmet medical needs within them. Additionally, both Big Pharma and Small Pharma companies are developing products in these fields. I compare these data sets statistically using Fisher's exact test and Yates' chi-square test. / by Daniel S. Rippy. / S.M.

Thesis (Ph.D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 2002. / Includes bibliographical references (p. 219-235). / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / The sensitivity and frequency selectivity of the hearing sense are determined primarily by mechanical properties of the cochlea. These mechanical properties are poorly understood in any species. This thesis contributes to our understanding of cochlear mechanics by presenting measurements of sound-induced motion of the alligator lizard cochlea. Novel methods were developed to maintain the cochlea in vitro for the time required to measure three-dimensional motions. Three-dimensional images of cochlear motion were taken by illuminating the cochlea with a light-emitting diode stroboscopically at predetermined phases of the acoustic stimulus. The resulting images were analyzed using computer vision algorithms to extract three-dimensional motions of all visible structures with nanometer precision. The sound-induced motion of the entire basilar papilla and of individual hair bundles of hair cells were simultaneously measured. The basilar papilla, in which the hair cells reside, moved as a rigid body, exhibiting simultaneous translational and rotational modes of motion. Both modes apply shearing forces to hair bundles. A simple mechanical model of the basilar papilla, based on these measurements, provides a physical basis for a mechanical low-pass filter hypothesized in previous models. In the tectorial region of the cochlea, motion of the tips of hair bundles and of the tectorial membrane (TM) were in phase with motion of the basilar papilla. None of the motions had significant frequency dependence, suggesting that this region does not exhibit appreciable mechanical frequency selectivity. In the free-standing region, which has no TM, hair bundle deflection depended on stimulus frequency and hair bundle height. / (cont.) At high frequencies, hair bundle deflection was proportional to basilar papilla displacement. At low frequencies, hair bundle deflection was proportional to a linear combination of basilar papilla velocity and acceleration. Measured hair bundle deflections were well fit by a simple hydrodynamic model (Freeman and Weiss, 1990) of this region of the cochlea. The measurements in this study provide the first characterization of the three-dimensional motion of all structures in a vertebrate cochlea. / by Alexander James Aranyosi. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2005. / Includes bibliographical references. / Drug-eluting stents have emerged as the most effective method for treating restenosis following percutaneous coronary interventions. This thesis investigates how drugs with similar physiochemical properties but different specific binding targets yield drastically different tissue transport, retention and ultimately efficacy independent of their putative biological effects. Our central hypothesis is that both specific and general binding of drugs to tissue proteins, as mediated by drug-specific physiochemical properties, plays a central role in arterial transport and distribution. We define and compare the kinetic and transport properties of clinically implemented compounds with different binding modes. While hydrophilic compounds are rapidly cleared, hydrophobic ones are retained with an arterial transmural distribution dependent upon the distribution of specific and general binding sites. Common systemically administered cardiac drugs compete with locally delivered agents through displacement of general binding sites. Exploration of drug binding in thrombus indicates significant specific and general binding capacity. Stent-to- arterial wall drug transfer is acutely sensitive to stent strut position in clot relative to the wall due to thrombus binding capacity. A poorly controlled microthrombotic environment around a stent strut can drastically enhance systemic washout while reducing delivery to the tissue. Together this body of work implies that specific and general binding plays a critical role in the clinical efficacy of locally delivered drugs, and must be a consideration in the rational design of stent-based delivery devices. / by Andrew D. Levin. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, February 2010. / "September 2009." Cataloged from PDF version of thesis. / Includes bibliographical references (p. 160-175). / This project is an experimental study of perceptual interactions between auditory and tactile stimuli. These experiments present vibrotactile stimuli to the fingertip and auditory tones diotically in broadband noise. Our hypothesis states that if the auditory and tactile systems integrate, the performance of the two sensory stimuli presented simultaneously will be different from the performance of the individual sensory stimuli. The research consists of work in two major areas: (1) Studies of the detection of auditory and tactile sinusoidal stimuli at levels near the threshold of perception (masked thresholds for auditory stimuli and absolute thresholds for tactile stimuli); and (2) Studies of loudness matching employing various combinations of auditory and tactile stimuli presented at supra-threshold levels. Results were compared to three models of auditory-tactile integration. The objective detection studies explore the effects of three major variables on perceptual integration: (a) the starting phase of the auditory relative to the tactile stimulus; (b) the temporal synchrony of stimulation within each of the two modalities; and (c) the frequency of stimulation within each modality. Detection performance for combined auditory-tactile (A+T) presentations was measured using stimulus levels that yielded 63%-77%-correct unimodal performance in a 2-Interval, 2-Alternative Forced- Choice procedure. Results for combined vibrotactile and auditory detection indicated: (1) For synchronous presentation of 500-msec, 250 Hz sinusoidal stimuli, percent-correct scores in the combined A+T conditions were significantly higher than scores within each single modality; / (cont.) (2) Scores in the A+T conditions were not affected by the relative phase of the 250 Hz auditory and tactile stimuli; (3) For asynchronous presentation of auditory and tactile 250 Hz stimuli, scores on the A+T conditions improved only when the tactile stimulus preceded the auditory stimulus (and not vice versa); and (4) The highest rates of detection in the combined-modality stimulus were obtained when stimulating frequencies in the two modalities were equal or closely spaced (and within the Pacinian range). The lack of phase effect suggests that integration operates on the envelopes rather than on temporal fine structure. The effects of asynchronous presentation imply a shorter time constant in the auditory compared to the tactile modality and are consistent with time constants deduced from single-modality masking experiments. The effects of frequency depend both on absolute frequency and on relative frequency of stimulation within each modality. In general, we found that an additive sensitivity model best explained detection performance when tones were presented synchronously and of the same frequency. In the second area of research, loudness matching was employed in a subjective study of the effects of frequency on auditory-tactile integration for stimuli presented at supra-threshold levels. These experiments, which were derived from previous auditory studies demonstrating the dependence of loudness on critical-band spacing of tonal signals, employed various combinations of auditory and tactile stimuli that were presented at equally loud levels in isolation. / (cont.) Loudness matches were obtained for auditory-only (A+A) and auditory-tactile (A+T) stimuli that were both close as well as farther apart in frequency. The results show that the matched loudness of an auditory pure tone is greater when the frequencies of combined stimuli (both A+A and A+T) are farther apart in frequency than when they are close in frequency. These results are consistent with the results found in the previous experiment exploring the frequency relationships at near-threshold levels, as well as with results in the psychoacoustic literature, and suggest that the auditory and tactile systems are interacting in a frequency-specific manner similar to the interactions of purely auditory stimuli. The research conducted here demonstrates objective and subjective perceptual effects that support the mounting anatomical and physiological evidence for interactions between the auditory and tactual sensory systems. / by E. Courtenay Wilson. / Ph.D.

Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2014. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 115-127). / Brain tumor associated edema, a common feature of malignant brain neoplasms, is a significant cause of morbidity from brain tumor. Systemic administration of corticosteroids, the standard of care, is highly effective but can introduce serious systemic complications. Agents that inhibit the vascular endothelial growth factor (VEGF) pathway, such as cediranib, are promising alternatives, but are also associated with systemic toxicity as VEGF is essential for normal physiological functions. A miniature drug delivery device was developed for local drug delivery in rodents. It comprises of a drug reservoir and a cap with orifice(s) through which drug is released. Drug release kinetics is dependent on the payload, the drug solubility, and the surface area for diffusion. Sustained releases of dexamethasone (DXM), dexamethasone sodium phosphate (DSP), and solid dispersion of cediranib (AZD/PVP) were achieved. Employing the solid dispersion technique to increase the solubility of cediranib was necessary to enhance its release. Therapeutic efficacy and systemic toxicity of local drug administration via our devices were examined in an intracranial 9L gliosarcoma rat model. Local delivery of DSP was effective in reducing edema but led to DXM induced weight loss at high doses in a pilot study. DXM, which is much less water-soluble than DSP, was used subsequently to reduce the dose delivered. The use of DXM enabled long-term, sustained zero-order release and a higher payload than DSP. Local deliveries of DXM and AZD/PVP were demonstrated to be as effective as systemic dosing in alleviating edema. Edema reduction was associated with survival benefit, despite continuous tumor progression. Animals treated with locally delivered DXM did not suffer from body weight loss and corticosterone suppression, which are adverse effects induced by systemic DXM. Local drug administration using our device is superior to traditional systemic administration as it minimizes systemic toxicity and allows increased drug concentration in the tumor by circumventing the blood brain barrier. A much lower dose can therefore be utilized to achieve similar efficacy. Our drug delivery system can be used with other therapeutic agents targeting brain tumor to achieve therapeutic efficacy without systemic toxicity. / by Qunya Ong. / Ph. D.

Thesis: Ph. D. in Bioinformatics and Integrative Genomics, Harvard-MIT Program in Health Sciences and Technology, 2016. / Cataloged from PDF version of thesis. / Includes bibliographical references. / Our genomes encode the molecular information that gives rise to life, yet we are just beginning to unravel how this information is organized, interpreted, and regulated. While the human genome contains -20,000 protein-coding genes, mammalian genomes also produce thousands of long non-coding RNAs (lncRNAs), some of which are now known to play essential roles in diverse biological processes including cellular differentiation and human disease. Recent studies show that many lncRNAs localize to the nucleus and interact with chromatin regulatory complexes, suggesting that some lncRNAs may represent a crucial missing component in our understanding of genome regulation. To test whether lncRNAs localize to and regulate specific sites in the genome, we developed genome-wide approaches to map lncRNA interactions with chromatin. Through studies of three conserved lncRNAs, we demonstrate that lncRNAs can exploit the three-dimensional architecture of the genome to identify their regulatory targets and, in turn, actively manipulate genome architecture to form subcompartments containing co-regulated genes. Thus, lncRNAs have unique capabilities as dynamic regulators that can locally amplify epigenetic signals. We next explored whether this model might apply to other long noncoding RNAs, many of which are not conserved across species and thus whose functions remain unclear. Through genetic dissection of their local regulatory functions, we show that many of these genomic loci participate in the local regulation of gene expression, but that these functions do not involve the IncRNA transcripts themselves. Instead, multiple mechanisms associated with RNA production including their promoters, the process of transcription, and RNA splicing - act in local networks of regulatory connections between spatially proximal genes, both protein-coding and noncoding. These findings reveal novel mechanistic explanations for the functions and evolution of noncoding transcription in mammalian genomes. Together these studies suggest a model in which mammalian gene regulation is organized into local neighborhoods defined by the spatial architecture of the genome. Within these neighborhoods, lncRNAs and DNA regulatory elements may function cooperatively to coordinate local gene expression. Dissecting this fundamental model for genome regulation may enable manipulation of the processes that interpret our genome sequence and galvanize efforts to develop new treatments for human disease. / by Jesse M. Engreitz. / Ph. D. in Bioinformatics and Integrative Genomics