Localization, Tissue Biology, And T Cell State — Implications For Cancer Immunotherapy, Jason M Schenkel, Kristen E Pauken

Faculty, Staff and Student Publications

Tissue localization is a critical determinant of T cell immunity. CD8+ T cells are contact-dependent killers, which requires them to physically be within the tissue of interest to kill peptide-MHC class I-bearing target cells. Following their migration and extravasation into tissues, T cells receive many extrinsic cues from the local microenvironment, and these signals shape T cell differentiation, fate and function. Because major organ systems are variable in their functions and compositions, they apply disparate pressures on T cells to adapt to the local microenvironment. Additional complexity arises in the context of malignant lesions (either primary or metastatic), and this …

Sackett And The Continued Atomization Of The Clean Water Act, Robert W. Adler

Case Western Reserve Law Review

No abstract provided.

Sackett V. Epa And The Regulatory, Property, And Human Rights-Based Strategies For Protecting American Waterways, Erin Ryan

Case Western Reserve Law Review

No abstract provided.

Friends With Co-Benefits: Defending The Epa’S Consideration Of Co-Benefits When Promulgating Clean Air Act Regulations, Casey E. Lindstrom

Case Western Reserve Law Review

No abstract provided.

Seasonal Change In The Avian Community Of A Western New York Shrub Swamp, James M. Berry, John Rappole Sr.

North American Bird Bander

No abstract provided.

Diversity And Body Condition Of Birds Inhabiting Native And Exotic Forests In The Pampas Of Argentina, Alejandro Baladrón

North American Bird Bander

No abstract provided.

State Of The Fisheries: Status Reports And Aquatic Resources Of Western Australia 2022/23, S.J. Newman, K.G. Santoro, D.J. Gaughan

Status Reports of the Fisheries and Aquatic Resources

Aquatic resources within Western Australia (WA) are in good condition, and this has positioned WA as a global leader in sustainable fisheries management. The sustainable fisheries of WA continue to support our strong economy and regional communities. Nonetheless, the lack of a consistent approach to build in the knowledge of Traditional Owners remains a gap in our longer term fisheries science in Western Australia.

Climate change and climate variability continues to impact fish stocks, challenging our ability to effectively monitor, assess, and manage fish stocks. We are continually working with our stakeholders, and the broader community to be adaptive, responsive, …

Enhanced Tp53 Reactivation Disrupts Myc Transcriptional Program And Overcomes Venetoclax Resistance In Acute Myeloid Leukemias, Yuki Nishida, Jo Ishizawa, Edward Ayoub, Rafael Heinz Montoya, Lauren B Ostermann, Muharrem Muftuoglu, Vivian R Ruvolo, Tallie Patsilevas, Darah A Scruggs, Shayaun Khazaei, Po Yee Mak, Wenjing Tao, Bing Z Carter, Steffen Boettcher, Benjamin L Ebert, Naval G Daver, Marina Konopleva, Takahiko Seki, Kensuke Kojima, Michael Andreeff

Faculty, Staff and Student Publications

The tumor suppressor TP53 is frequently inactivated in a mutation-independent manner in cancers and is reactivated by inhibiting its negative regulators. We here cotarget MDM2 and the nuclear exporter XPO1 to maximize transcriptional activity of p53. MDM2/XPO1 inhibition accumulated nuclear p53 and elicited a 25- to 60-fold increase of its transcriptional targets. TP53 regulates MYC, and MDM2/XPO1 inhibition disrupted the c-MYC-regulated transcriptome, resulting in the synergistic induction of apoptosis in acute myeloid leukemia (AML). Unexpectedly, venetoclax-resistant AMLs express high levels of c-MYC and are vulnerable to MDM2/XPO1 inhibition in vivo. However, AML cells persisting after MDM2/XPO1 inhibition exhibit a …

Companion Crops Alter Olfactory Responses Of The Fall Armyworm (Spodoptera Frugiperda) And Its Larval Endoparasitoid (Cotesia Icipe), Emmanuel Peter, Amanuel Tamiru, Subramanian Sevgan, Thomas Dubois, Segenet Kelemu, Kerstin Kruger, Baldwyn Torto, Abdullahi Yusuf

All Peer-Reviewed Publications

Background: The fall armyworm (FAW), Spodoptera frugiperda, is a devastating invasive pest and a threat to food security in Africa, with yield losses of 20–50%. Recent studies highlighted the importance of cereal crops such as maize and sorghum as the most preferred host plants for FAW oviposition. In the current work, we investigated the olfactory responses of FAW and its key larval endoparasitoid Cotesia icipe to odours from the preferred host (maize) in the presence of six potential companion crops including beans, groundnut, sweet potato, greenleaf- and silverleaf desmodium, and cassava. We hypothesized that odours released by companion crops in …

Huntington Study Group's Neuropsychology Working Group: Implementing Non-Motor Diagnostic Criteria, Ciaran M Considine, M Agustina Rossetti, Victor A Del Bene, Kendra Anderson, Sharlet A Anderson, Andrea S Celka, Mary C Edmondson, Amelia L Nelson-Sheese, Adam Piccolino, Antonio L Teixeira, Julie C Stout

Faculty, Staff and Student Publications

Background: The clinical diagnosis of manifest Huntington's disease (HD) relies on a high level of clinical confidence (99% confidence) of HD-consistent motor signs. Longitudinal data have reliably identified cognitive and behavioral dysfunction predating clinical motor diagnosis by up to 15 years. Reliance on motor signs to establish a diagnosis of HD increases risk of early misdiagnosis or delayed diagnosis. Clinical neuropsychologists are uniquely positioned to advise on the clinical application of the Movement Disorder Society Task Force's recently proposed non-motor diagnostic criteria for HD.

Objectives: To provide (1) a recommended clinical approach toward non-motor diagnostic criteria in persons with HD …

Relapse Recovery In Relapsing-Remitting Multiple Sclerosis: An Analysis Of The Combirx Dataset, Marcus W Koch, Ester Moral, Luis Brieva, Jop Mostert, Eva Mm Strijbis, Jacynthe Comtois, Pavle Repovic, James D Bowen, Jerry S Wolinsky, Fred D Lublin, Gary Cutter

Faculty, Staff and Student Publications

BACKGROUND: Clinical relapses are the defining feature of relapsing forms of multiple sclerosis (MS), but relatively little is known about the time course of relapse recovery.

OBJECTIVE: The aim of this study was to investigate the time course of and patient factors associated with the speed and success of relapse recovery in people with relapsing-remitting MS (RRMS).

METHODS: Using data from CombiRx, a large RRMS trial (clinicaltrials.gov identifier NCT00211887), we measured the time to recovery from the first on-trial relapse. We used Kaplan-Meier survival analyses and Cox regression models to investigate the association of patient factors with the time to …

Systematic Review And Meta-Analysis Of The Association Between Radiation Therapy Treatment Volume And Patient Outcomes, Jerry Ye Aung Kyaw, Alice Rendall, Erin F Gillespie, Tom Roques, Laurence Court, Yolande Lievens, Alison C Tree, Chris Frampton, Ajay Aggarwal

Faculty, Staff and Student Publications

Purpose: Evidence of a volume-outcome association in cancer surgery has shaped the centralization of cancer services; however, it is unknown whether a similar association exists for radiation therapy. The objective of this study was to determine the association between radiation therapy treatment volume and patient outcomes.

Methods and materials: This systematic review and meta-analysis included studies that compared outcomes of patients who underwent definitive radiation therapy at high-volume radiation therapy facilities (HVRFs) versus low-volume facilities (LVRFs). The systematic review used Ovid MEDLINE and Embase. For the meta-analysis, a random effects model was used. Absolute effects and hazard ratios (HRs) were …

An Update On The Management Of Advanced Phase Chronic Myeloid Leukemia, Nicholas J Short, Jayastu Senapati, Elias Jabbour

Faculty, Staff and Student Publications

Purpose of review: While most patients with chronic myeloid leukemia (CML) present in a chronic phase and are expected to have a normal life expectancy, some patients present with or progress to a more aggressive accelerated phase (AP) or blast phase (BP) of CML. Herein, we discuss the diagnostic considerations of advanced phase CML and review its contemporary management.

Recent findings: Later-generation, more potent BCR::ABL1 tyrosine kinase inhibitors (TKIs) such as ponatinib may result in superior outcomes in patients with advanced phase CML. For CML-BP, combination approaches directed against the blast immunophenotype appear superior to TKI monotherapy. The role of …

Evaluation Of Potential Role Of R-Loop And G-Quadruplex Dna In The Fragility Of C-Myc During Chromosomal Translocation Associated With Burkitt's Lymphoma, Nitu Kumari, Kohal Das, Shivangi Sharma, Sumedha Dahal, Sagar Sanjiv Desai, Urbi Roy, Anju Sharma, Meghana Manjunath, Vidya Gopalakrishnan, S T Retheesh, Saniya M Javadekar, Bibha Choudhary, Sathees C Raghavan

Faculty, Staff and Student Publications

t(8;14) translocation is the hallmark of Burkitt's lymphoma and results in c-MYC deregulation. During the translocation, c-MYC gene on chromosome 8 gets juxtaposed to the Ig switch regions on chromosome 14. Although the promoter of c-MYC has been investigated for its mechanism of fragility, little is known about other c-MYC breakpoint regions. We have analyzed the translocation break points at the exon 1/intron 1 of c-MYC locus from patients with Burkitt's lymphoma. Results showed that the breakpoint region, when present on a plasmid, could fold into an R-loop confirmation in a transcription-dependent manner. Sodium bisulfite modification assay revealed significant single-strandedness …

The Risk Index As A Basis For Risk/Benefit Analyses And Protocol Optimization In Diagnostic Nuclear Imaging, Juan C Ocampo Ramos, Lukas M Carter, Justin L Brown, Harry Marquis, Carlos F Uribe, Pat B Zanzonico, Wesley E Bolch, Adam L Kesner

Faculty, Staff and Student Publications

Background: Potential risk associated with low-dose radiation exposures is often expressed using the effective dose (E) quantity. Other risk-related quantities have been proposed as alternatives. The recently introduced risk index (RI) shares similarities with E but expands the metric to incorporate medical imaging-appropriate risks factors including patient-specific size, age, and sex.

Purpose: The aim of this work is to examine the RI metric for quantifying stochastic radiation risk and demonstrate its applications in nuclear imaging. The advantages in this improved metric may help the field progress toward stratified risk consideration in the course of patient management, improve efforts for procedure …

Droid: Dose-Ranging Approach To Optimizing Dose In Oncology Drug Development, Beibei Guo, Ying Yuan

Faculty, Staff and Student Publications

In the era of targeted therapy, there has been increasing concern about the development of oncology drugs based on the "more is better" paradigm, developed decades ago for chemotherapy. Recently, the US Food and Drug Administration (FDA) initiated Project Optimus to reform the dose optimization and dose selection paradigm in oncology drug development. To accommodate this paradigm shifting, we propose a dose-ranging approach to optimizing dose (DROID) for oncology trials with targeted drugs. DROID leverages the well-established dose-ranging study framework, which has been routinely used to develop non-oncology drugs for decades, and bridges it with established oncology dose-finding designs to …

Radiation-Induced Innate Neutrophil Response In Tumor Is Mediated By The Cxcls/Cxcr2 Axis, Faya Zhang, Oscar Mulvaney, Erica Salcedo, Subrata Manna, James Z Zhu, Tao Wang, Chul Ahn, Laurentiu M Pop, Raquibul Hannan

Faculty, Staff and Student Publications

The early events that lead to the inflammatory and immune-modulatory effects of radiation therapy (RT) in the tumor microenvironment (TME) after its DNA damage response activating the innate DNA-sensing pathways are largely unknown. Neutrophilic infiltration into the TME in response to RT is an early innate inflammatory response that occurs within 24-48 h. Using two different syngeneic murine tumor models (RM-9 and MC-38), we demonstrated that CXCR2 blockade significantly reduced RT-induced neutrophilic infiltration. CXCR2 blockade showed the same effects on RT-induced tumor inhibition and host survival as direct neutrophil depletion. Neutrophils highly and preferentially expressed CXCR2 compared to other immune …

Aspects Of Stochastic Geometric Mechanics In Molecular Biophysics, David Frost

All Dissertations

In confocal single-molecule FRET experiments, the joint distribution of FRET efficiency and donor lifetime distribution can reveal underlying molecular conformational dynamics via deviation from their theoretical Forster relationship. This shift is referred to as a dynamic shift. In this study, we investigate the influence of the free energy landscape in protein conformational dynamics on the dynamic shift by simulation of the associated continuum reaction coordinate Langevin dynamics, yielding a deeper understanding of the dynamic and structural information in the joint FRET efficiency and donor lifetime distribution. We develop novel Langevin models for the dye linker dynamics, including rotational dynamics, based …

Assessing Chondrocyte Viability Of Articular Cartilage Using Label-Free Imaging Methods, Hongming Fan

All Dissertations

ABSTRACT

Articular cartilage covers the ends of bones, providing a protective layer that can endure forces during movement. Chondrocytes, the only cell type found in articular cartilage, produce collagen fibers and proteoglycans that maintain the extracellular matrix (ECM). Cartilage damage impairs chondrocytes and their ability to maintain tissue stability. There are various factors that can cause cell death, which can be broadly classified into two categories: programmed cell death (apoptosis) and non-programmed cell death (necrosis). The consequences of cell death can have significant impacts on the extracellular matrix (ECM). The ECM is a complex network of proteins and carbohydrates that …

Genome-Wide Significant Risk Loci For Mood Disorders In The Old Order Amish Founder Population, Elizabeth M. Humphries, Kwangmi Ahn, Rachel L. Kember, Fabiana L. Lopes, Evelina Mocci, Juan M. Peralta, John Blangero, David C. Glahn, Fernando S. Goes, Peter P. Zandi

School of Medicine Publications

Genome-wide association studies (GWAS) of mood disorders in large case-control cohorts have identified numerous risk loci, yet pathophysiological mechanisms remain elusive, primarily due to the very small effects of common variants. We sought to discover risk variants with larger effects by conducting a genome-wide association study of mood disorders in a founder population, the Old Order Amish (OOA, n = 1,672). Our analysis revealed four genome-wide significant risk loci, all of which were associated with >2-fold relative risk. Quantitative behavioral and neurocognitive assessments (n = 314) revealed effects of risk variants on sub-clinical depressive symptoms and information processing speed. …

An In Vitro Platform To Characterize Myocardial Wound Remodeling, Jonathan Heywood

All Dissertations

Heart Failure, sometimes called Congestive Heart Failure, is a collection of pathological disruptions in which the heart is unable to pump blood properly. It affects over 6 million people in the United States, with the cost-per-patient at approximately $30,000 and the total cost estimated to be $160 billion by 2030. There is no single cause of heart failure, as it can manifest as a varying array of diseases, disorders, and syndromes. However, many of these underlying diseases result specifically from dysregulation of mechanically active cells called cardiac fibroblasts, which play a critical role in the remodeling of the extracellular matrix …

Influence Of Access To Public Parks On Mortality Among Older Adults In The United States, Jiaying Dong

All Dissertations

Research shows the health benefits of green spaces are universal, but there's a noticeable disparity in their distribution in the U.S., especially between urban and rural areas. Marginalized groups, particularly those of lower economic status or racial minorities, often have limited access to these spaces. This inequity could be more impactful on the elderly, who are more vulnerable to health issues. However, specific health benefits of green spaces for seniors are not well defined. This study examines the correlation between park access, mortality in those over 65, and income disparities across all U.S. counties.

The study employed a quantitative approach …

Physics-Based Machine Learning Methods For Control And Sensing In Fish-Like Robots, Colin Rodwell

All Dissertations

Underwater robots are important for the construction and maintenance of underwater infrastructure, underwater resource extraction, and defense. However, they currently fall far behind biological swimmers such as fish in agility, efficiency, and sensing capabilities. As a result, mimicking the capabilities of biological swimmers has become an area of significant research interest. In this work, we focus specifically on improving the control and sensing capabilities of fish-like robots.

Our control work focuses on using the Chaplygin sleigh, a two-dimensional nonholonomic system which has been used to model fish-like swimming, as part of a curriculum to train a reinforcement learning agent to …

How Is Wildlife Poaching Changing In Uganda And How Can We Understand The Contribution Of Wildlife Protection Efforts At Multiple Scales: Murchison Falls National Park, Uganda., Ingrid Nyonza Nyakabwa

All Dissertations

Wildlife poaching is a critical global issue that poses significant threats to biodiversity, ecological balance, and the long-term sustainability of wildlife in Sub-Saharan Africa. The illicit trade in wildlife and their derivatives continues to grow, fueled by various socio-economic, cultural, and environmental factors. As the demand for wildlife products persists, it is imperative to understand the underlying causes, impacts, and potential solutions to combat this detrimental practice.

This research examined the dimensions of wildlife poaching in and around the area of Murchison Falls National Park in Uganda, the largest and oldest National Park in Uganda. Uganda has experienced success in …

Multidimensional Chromatographic Coupling Strategies Implementing Capillary-Channeled Polymer Fiber Stationary Phases, Sarah Wysor

All Dissertations

Liquid chromatography (LC) is a widely employed technique in analytical separations due to the ease of implementing rapid analysis methods to isolate targeted analytes. While LC is commonplace, challenges often arise with complex macromolecules as it often effects isolation via only one attribute of the targeted analyte (i.e., physical, chemical). To cater to increasingly complex samples requiring multiple chromatographic workflows, two-dimensional liquid chromatography (2DLC) has emerged. Various applications, such as drug discovery, pharmaceutical manufacturing, and specialty chemical manufacturing, require highly pure final products for release to the market. Consequently, multiple chromatographic steps are necessary for isolation and purification. Within pharmaceuticals, …

Biochemical Analyses Of Udgx-A Crosslinking Uracil-Dna Glycosylase, Chuan Liang

All Dissertations

DNA base damage is common due to exposure to various endogenous and exogenous factors. To repair the base lesions, such as uracil from cytosine deamination, enzymes from the uracil-DNA glycosylase (UDG) superfamily are critical, which can recognize the damaged base and initiate the base excision repair (BER) pathway. There used to be six families of proteins identified in the UDG superfamily until a new member, UDGX, was found in Mycobacterium smegmatis, which is a unique DNA-crosslinking UDG. In this dissertation work, a series of biochemical analyses of the newly found UDGX are performed, including the analyses of structures, functions, …

The Use Of The South Carolina School Improvement Model - Quick Cycles In Sixth-Grade Science Classrooms, Jennifer Gnann

All Dissertations

Using data to make informed decisions about instruction strengthens a teacher’s delivery of content within the classroom. However, many teachers have not been taught how to properly use a model of rapid improvement cycles to analyze data and apply it to their classroom instruction. I modified the South Carolina School Improvement Model so that it could be used in short cycles to see how teachers used it to plan for, monitor, and adjust instruction in their classrooms.

I conducted a single case study over a six-week period in which I instructed two sixth-grade science teachers on how to use the …

Delineating The Impact Of Vascular Smooth Muscle Cell Abca1/G1 And Mir-33a Expression On Atherosclerosis, Olanrewaju Oladosu

All Dissertations

Atherosclerotic cardiovascular disease is the leading cause of mortality worldwide due to being the predominant factor in heart attack and stroke deaths. Atherosclerotic cardiovascular disease is caused by cholesterol accumulating in arteries. It is historically thought that the cell type most responsible for causing atherosclerosis via excessive cholesterol accumulation is intimal monocyte-derived macrophages. However, macrophage-like cells (MLC) of vascular smooth muscle cell (VSMC) origin have now been proposed as another cell type to trigger atherosclerosis, since VSMC cholesterol accumulation results in these cells to trans-differentiate into a MLC phenotype. Three major genes involved in cholesterol metabolism are ABCA1, ABCG1, and …

Enhancing Security And Performance Of Deep Neural Networks, Azadeh Gholamrezazadeh Famili

All Dissertations

The significance of security is often overlooked until a catastrophic event occurs. This holds for the security of existing IoT devices. Numerous devices have been deployed and repurposed without adequately considering their security vulnerabilities. There is a lack of comprehensive security protocols for devices that frequently interact with one another. Even in emerging fields like machine learning (ML), which has found extensive applications in strategy optimization, decision-making, data classification, and other domains, discussions around security vulnerabilities are not widespread. Regarding security in ML, the focus tends to revolve around specific topics such as adversarial attacks. However, due to the remarkable …

Making The Move Toward Meaningfulness In Learning Activities: Enhancing Teacher Self-Efficacy In Student Engagement Through An Instructional Coaching Approach In Improvement Science, Maureen Tiller

All Dissertations

Student engagement is a common problem in schools today and a challenging one to solve. Choosing to dive deeper into this complex problem at one high school, ten teachers participated in a coaching cycle designed to impact self-efficacy in student engagement with the support of the school’s instructional coach in collaboration with the principal. One overarching research question guided this improvement science study: What impact does an instructional coaching cycle focused on meaningfulness in learning activities have on teachers’ self-efficacy in student engagement? To answer the research question, I conducted a quantitative and qualitative data analysis of pre- and …