Therapeutic Potential of TRP Channels in the Targeting of Rheumatoid Arthritis Synovial Fibroblasts

Rheumatoid arthritis is a chronic inflammatory disease primarily affecting the synovium, articular cartilage, and bone within a joint, but it is a unique form of arthritis wherein effects are systemic. The cause of this autoimmune disease remains unknown, but there are many environmental and genetic factors that play into susceptibility. Research is still far from drug-free remission despite great advancements over the past few decades. The majority of therapies developed rely on immunosuppressant or immunomodulator molecules and come with risk of infection, high costs, and toxic, uncontrolled side effects. Those diagnosed maintain a significant unmet need for targeted therapies. There is increasing evidence towards non-immune cell types in the joint as the culprit for the changes in anatomy of the joint at disease onset. A thin lining called the synovium covers the joint cartilage and acts as a barrier which secretes synovial fluid that lubricates the joint. Synovial fibroblasts, also called fibroblast-like synoviocytes, are responsible for this secretion of lubricating components hyaluronic acid and lubricin that allow for ease of movement. Together with macrophages, they make up the synovial lining and sub-lining in roughly equal proportion. Proinflammatory cytokine production in the inflamed joint leads to synovial fibroblast proliferation and transforms these cells into a “tumor-like” phenotype with the capacity to degrade cartilage and bone. Synovial fibroblasts perpetuate the destruction of articular cartilage by producing matrix-degrading enzymes, cytokines, and increasing production of adhesion molecules to attach and build on to cartilage. The synovium thickens and the cartilage and bone in the joint is broken down, and synovial fibroblasts recruit more immune cells to the joint to further exacerbate joint destruction. This positive feedback loop makes synovial fibroblasts a desirable target for anti-rheumatic drugs An abundance of research implicating TRP channels in rheumatoid arthritis synovial fibroblasts pathogenic phenotype has accumulated over the past decade. Studies of the rheumatoid synovium demonstrate the expression of several of these channels including TRPV1, TRPV2, TRPV4, TRPA1, TRPM7, TRPM8, and more. The channels’ direct implication in synovial fibroblast aggressive phenotype is becoming better understood and shows promise for TRP channels as therapeutic targets. My master’s thesis will focus on TRP channel involvement in mechanisms by which synovial fibroblasts evade apoptosis, proliferate, degrade the joint, and migrate to unaffected joints in order to understand these biological sensors as potential rheumatoid arthritis therapeutic candidates

Short-Term Outcomes And Long-Term Prognosis In Oral Cavity Cancer

SHORT-TERM OUTCOMES AND LONG-TERM PROGNOSIS OF ORAL CAVITY CANCER. Zachary G. Schwam, Benjamin L. Judson (advisor). Section of Otolaryngology, Department of Surgery, Yale University School of Medicine, New Haven, CT. We sought to characterize short-term morbidity and mortality outcomes as well as long-term changes in prognosis for oral cancer patients. We predicted that clinical and demographic variables would affect short- and long-term outcomes. Retrospective analyses of the National Surgical Quality Improvement Program (NSQIP) and National Cancer Database (NCDB) were performed on 408 and 13,655 patients, respectively. Chi-square, Kaplan Meier, logistic regression, and Cox proportional hazards regression were performed. In the NSQIP, the overall adverse event and mortality rates were 20.3% and 1.0%, respectively. The most common complications were reoperation, infection, and respiratory complications. Over 90% of post-discharge complications occurred by post-discharge day (PDD) 14, but the majority of surgical-site infections and dehiscences occurred by PDD 7. Neck dissection, smoking, and weight loss were associated with several complications in multivariate analysis. In the NCDB, three-year overall survival increased by 36.2% and 16.0% for patients with early and late stage disease (LSD), respectively. In LSD patients, adjuvant chemoradiotherapy increased from 8.3% to 36.4%. Later year of diagnosis (hazard ratio [HR] 0.76), neck dissection (HR 0.90), and negative margins (HR 1.00) were associated with better overall survival (all p≤.002). Many patients with oral cavity cancers experience postoperative complications, some of which occur post-discharge. Early follow-up should be sought for high-risk patients. Long-term prognosis for oral cancers has increased dramatically, as has the administration of adjuvant chemoradiotherapy in LSD. Numerous sociodemographic, clinical, and treatment variables may account for this difference in survival

Understanding Self-regulated Learning

Over the past few decades, self-regulated learning (SRL) has been an area of research that continues to grow in importance due to its strong relationship with academic success (Zimmerman, Bandura, & Martinez-Pons, 1992; Zimmerman & Kitsantas, 1997). Its early development arose through the metacognitive and social-cognitive literature with research geared towards a better understanding of successful learning. Over the years, confusion has grown over the conceptual definition of SRL, leading to a vast array of literature researching many of its sub-components and processes of metacognition and motivation. Two researchers in the area of SRL, Pintrich (1999, 2000, 2004) and Zimmerman (1989, 2000, 2002), have greatly contributed to our current understanding. Through their writings, a conceptual model was developed to include multiple assumptions, phases, and domains. Studies exploring individual differences have led to the challenging task of developing a measure of SRL. The two most popular questionnaires are the Motivated Strategies for Learning Questionnaire (MSLQ; Pintrich, Smith, Garcia, & McKeachie, 1991) and the Learning and Study Strategies Inventory (Weinstein & Palmer, 2002). With an increase in online learning, the Online Self-regulated Learning Questionnaire (OSLQ; Barnard, Lan, To, Paton, & Lai, 2009) was developed to measure SRL in the online environment. Barnard-Brak, Lan, and Paton (2010) using the OSLQ identified five profiles of SRL and related these profiles to academic success. This current study set out to replicate the design and findings of Barnard-Brak et al. (2010) in a traditional university setting with 477 students of traditional age attending online classes. Additionally, the current study explored the possible relationship of age, level of education, online learning experience, and online comfort with the identified self-regulated learning profiles. While the current study did not find the same five profiles, four profiles were found that demonstrate that students use varying levels of the skills associated with SRL. Relationships were not found between the four profiles and academic success, age, level of education, or online experience. Level of comfort of the online environment appeared to have an impact on profile membership as did gender

Not My Privilege: How Construal Level Explains Reactions to Male Privilege

Awareness of one’s privilege has been shown to evoke feelings of defensiveness or collective guilt, particularly when one’s privileged identity is highly central to their sense of self. Research on privilege indicates that people may psychologically distance themselves from the notion of privilege in order to protect themselves from its potentially threatening manner (Phillips & Lowery, 2015). Construal level theory states that concepts that are more psychologically close are construed in more concrete terms whereas concepts that are more psychologically distant are construed as more abstract (Trope & Liberman, 2010). In the present study, 246 male participants were assessed for the importance of their male identity and were then primed with either a close or distant construal mindset. They were then randomly assigned to read about privilege or to read neutral statements. Afterwards, participants’ reactions were assessed including levels of defensiveness and collective guilt. Results indicated that male identity did not interact with construal condition or privilege condition to predict reactions to male privilege. However, participants’ political orientation did interact with privilege condition and construal level, such that when primed with a close construal level, liberal participants were more likely to respond with collective guilt when made aware of their privilege in comparison to conservative participants. Implications and possible explanations for the lack of anticipated effects are discussed

Characteristics of Executive Functioning in a Small Sample of Children with Tourette Syndrome

Tourette Syndrome (TS) is a disorder that involves at least one vocal tic and two or more motor tics, however associated symptoms of Obsessive Compulsive Disorder (OCD) and Attention Deficit Disorder with or without hyperactivity (ADHD) are common. Many children with TS exhibit educational difficulties and one possible explanation may be deficits in executive functioning. The focus of this study was to look at the severity of symptoms often associated with TS (tics, OCS, and ADHD symptoms) and its potential relationship with the Behavior Rating Inventory of Executive Function (BRIEF) parent form in eleven children diagnosed with Tourette syndrome, ages 8-14. The BRIEF was completed by the parent of the child along with symptom measures evaluating tics, obsessive-compulsive behaviors and attention deficit symptoms. Despite relative low mean scores on the symptom measures and just a few children exhibiting clinically significant scores on the BRIEF indexes, at least half the children exhibited abnormal scores on the working memory, inhibit, and shift subscales on the BRIEF. Varying patterns of relationships were found on the BRIEF subscales for each symptom severity scales. Results suggest that the BRIEF may be useful in determining the specific areas of difficulty in a population with variable symptomatology

Essays on the Motivations and Behavior of Individual Political Donors

This dissertation consists of three related essays on the motivations and behavior of individual political donors. These essays test theoretical predictions from the campaign finance and political behavior literature using field experiments and a natural experiment, bolstering the causal interpretation of the findings. The first essay reports the results of a field experiment examining the effect of political information on the decision to contribute. In advance of the November 2014 election, postcards with information about the major party candidates for Ohio governor and secretary of state were mailed to nearly 40,000 randomly selected likely donors in Ohio. The messages in these mailings, seven in all, provided factual information regarding campaign fundraising and endorsements, as well as a simple election reminder. Notably, the messages did not include encouragements to donate or partisan cues. The experimental results show that partisan donors respond to electoral threats as well as electoral opportunities under different conditions. Donors are more likely to give to the stronger candidate when they receive a simple election reminder with no fundraising information. But when donors see which candidates are ahead and behind in total fundraising, donors give more to the candidate who is behind while donations to the candidate with more money are unaffected. The results show that donors respond to objective information about fundraising weakness in order to help their preferred candidate. The second essay (co-authored) uses experimental designs to explore two possible paths to expanding the number of small donors. First, we examine whether nonpartisan appeals, of the kind that nonprofit groups or governments could use, expand the donor base. The results suggest that one type of nonpartisan message represents a promising fundraising appeal: encouraging subjects to contribute in order to keep elected officials focused on policy issues of importance to the potential donor. Second, we determine whether informing the public about existing incentives for making small contributions increases the number and size of contributions. We report the results of two field experiments that randomly provided information to likely donors about municipal- and state-level incentives for making political contributions. Across the two experiments, we find little evidence that information about contribution incentives increases giving. The third essay examines the effect of presidential political advertisements on contributing to the presidential campaigns of the major party candidates. I examine the effect of aggregate political advertising on aggregate contributing at the media zone level, and also estimate the effects of each party’s advertisements separately on giving to the party’s presidential campaign. I find that aggregate advertisements may have an effect on aggregate giving, but this effect is substantively small (much smaller than previous scholars have found) and inconsistent across different model specifications. In addition, I find that examining aggregate amounts may mask differences between the parties. During the 2008 election, Democratic presidential advertisements had a small, but detectable, positive effect on giving to the Democratic campaign. By contrast, Republican advertisements did not significantly increase giving to the Republican campaign in 2008

Space Retrieval Training for Memory Enhancement in Adults with Dementia

The final portfolio contains 8 research articles from national and international journals. Study designs include one systematic review, one randomized control trial with pretest-posttest design, three small-scale randomized control trials, one quasi-experimental study with no control, one time-series study, and one case study. All studies relate directly to components of the evidence-based practice question and will be used to draft new recommendations for implementation regarding spaced retrieval training for memory enhancement in adults with dementia. Seven out of the eight articles looked at the effects of SR techniques on functional tasks. Articles looked at eating difficulty (1), independent use of walkers (1), iADL function (3), use of technology (1), and ADL function (1). One out of eight articles looked at benefits of spaced retrieval techniques on episodic memory, which is not necessarily a functional task, but is needed to perform functional tasks

Die Materials for Critical Applications and Increased Production Rates

Die materials for aluminum die-casting need to be resistant to heat checking, and have good resistance to washout and to soldering in a fast flow of molten aluminum. To resist heat checking, die materials should have a low coefficient of thermal expansion, high thermal conductivity, high hot yield strength, good temper softening resistance, high creep strength, and adequate ductility. To resist the washout and soldering, die materials should have high hot hardness, good temper resistance, low solubility in molten aluminum and good oxidation resistance. It is difficult for one material to satisfy with all above requirements. In practice, H13 steel is the most popular material for aluminum die casting dies. While it is not an ideal choice, it is substantially less expensive to use than alternative materials. However, in very demanding applications, it is sometimes necessary to use alternative materials to ensure a reasonable die life. Copper-base, nickel-base alloys and superalloys, titanium-,molybdenum-, tungsten-base alloys, and to some extent yttrium and niobium alloys, have all been considered as potential materials for demanding die casting applications. Most of these alloys exhibit superior thermal fatigue resistance, but suffer from other shortcomings

Effect of Composition and Processing on the Thermal Fatigue and Toughness of High Performance Die Steels. Year 1 Report

The goal of this project is to extend the lifetime of dies for die casting by 20%. Since the die contributes about 10% to the cost of die cast parts, such an improvement in lifetime would result in annual savings of over $200 Million dollars. This is based on the estimated annual die production of one Billion dollars in the US. The major tasks of this two year project are: (1) Evaluate NEW DIE STEEL COMPOSITIONS that have been developed for demanding applications and compare them to Premium Grade H-13 die steel. (2) Optimize the AUSTENITIZING TREATMENT of the new composition. Assess the effects of fast, medium and slow COOLING RATES DURING HEAT TREATMENT, on the thermal fatigue resistance and toughness of the die steel. (3) Determine the effect of ELECTRO-DISCHARGE MACHINING (EDM) on the thermal fatigue resistance and impact properties of the steel. (4) Select demanding components and conduct IN-PLANT TESTING by using the new steel. Compare the performance of the new steel with identical components made of Premium Grade H-13. The immersion thermal fatigue specimen developed at CWRU is being used to determine resistance to heat checking, and the Charpy V-notch test for evaluating the toughness. The overall result of this project will be identification of the best steel available on the market and the best processing methods for aluminum die casting dies. This is an interim report for year 1 of the project

Effect of Composition and Processing on the Thermal Fatigue and Toughness of High Performance Die Steels. Final Report

The objective of this study was to improve average die life by optimizing die steel composition and the die processing. Four different steels, K,Q,C and Premium Grade H-13 have been investigated for thermal fatigue resistance and toughness. Optimum heat treatment processing has been determined for each steel with respect to austenitizing temperature and tempering conditions. The effect of the quenching rate on the thermal fatigue resistance and toughness of the die steels and the effect of Electro-Discharge Machining (EDM) on the thermal fatigue resistance were also determined. The immersion thermal fatigue specimen developed at CWRU was used to determine the thermal fatigue resistance as characterized by the two parameters of average maximum crack length and total crack area. The Charpy V-notch impact test was used over a -100{degrees}F to 450{degrees}F testing temperature range to evaluate the toughness and the brittle-ductile transition behavior. K steel has been identified as superior in performance compared to Premium Grade H-13. Q and C provide lower toughness and thermal fatigue resistance than H-13. Faster cooling rates provide higher thermal fatigue resistance and toughness. Higher austenitizing temperatures such as 1925{degrees}F compared to 1875{degrees}F provide better thermal fatigue resistance, but lower austenitizing temperatures of 1875{degrees}F provide better toughness. Higher hardness improves thermal fatigue resistance, but reduces toughness. A minimum of Rc 46 hardness is desired for aluminum die casting dies. EDM reduces the thermal fatigue resistance compared to conventional machining operations. When the EDM process of multiple small steps of decreasing energy and post-EDM treatments are employed, the effect can be reduced to a very slight amount. Preliminary evidence of the superior performance of the K steel has been provided by ongoing field testing of inserts in multiple cavity dies