Digital Commons Network^™

Addressing Health Disparities In Hematologic Malignancies: From Genes To Outreach, Christopher R Flowers, Rachel W Anantha, Veronica Leautaud, Pinkal Desai, Chancellor E Donald, Michelle A T Hildebrandt, Jean L Koff, Rulla M Tamimi, Wendy Cozen, Chijioke Nze, Ari M Melnick

Faculty, Staff and Student Publications

This review underscores our shared responsibility to champion multidimensional strategies rooted in basic and translational science, community involvement, and societal responsiveness for a meaningful impact. Unifying themes include the need to enhance collaborative infrastructure to engage laboratory researchers, epidemiologists, data scientists, clinicians, patients, community leaders, and policymakers; patient-level support services; outreach, education, and navigation for patients at the community level; recruitment and retention of underrepresented groups in the healthcare and research workforce; and funding for these efforts.

Gut-Spine Connection: Unexplored Pathways To Improving Outcomes In Spinal Health And Disease, Anesu K. Murambadoro, Julia Saifetiarova, Priya Kale, Victor A. Bob-Yellowe, Paul Bonilla, Aun A. Bangash, Isabella Ortigoza, Anjana Ganesh, Mohammed S. Razzaque

Research Symposium

Introduction: Lumbar spinal fusion is among the most expensive procedures in the Medicare system, with costs exceeding $33 billion annually. Improving recovery outcomes for these procedures is critical, and emerging research suggests that microbiome-targeted therapies could play a key role. There is growing evidence linking spinal health with gut microbiota alterations, particularly through the gut-spine axis, which involves the gut-disc, gut-bone, and gut-immune interactions. This bidirectional relationship between gut microbiota and spinal health offers a novel approach for understanding recovery mechanisms. Additionally, magnesium deficiency, which is prevalent, may exacerbate both gut dysbiosis and poor bone health, contributing to chronic skeletal …

Gain-Of-Function Chromatin Remodeling Activity Of Oncogenic Foxl2c134w Reprograms Glucocorticoid Receptor Occupancy To Drive Granulosa Cell Tumors, Thomas Welte, Veena K Vuttaradhi, Eleonora Y Khlebus, Allison Brodsky, Alejandra Flores Legarreta, Joseph Celestino, Reid T Powell, Clifford C Stephan, Nghi Nguyen, Jian Li, Shiro Takamatsu, Katherine Calzoncinth, Anil K Sood, David M Gershenson, P Andrew Futreal, Barrett Lawson, R Tyler Hillman

Faculty, Staff and Student Publications

Adult type ovarian granulosa cell tumors (AGCT) are rare malignancies with the near universal c.C402G (p.Cys134Trp) somatic mutation in FOXL2, a forkhead box family transcription factor important for ovarian function. Relapsed AGCT is incurable, but the mechanism of the unique FOXL2 mutation could confer therapeutic vulnerabilities. To identify FOXL2C134W-dependent pharmacologic synergies, we created and characterized endogenous FOXL2 isogenic AGCT cells and an AGCT tumoroid biobank. A drug screen identified that glucocorticoids promote FOXL2C134W-dependent AGCT growth. Epigenetic investigation revealed that the Cys134Trp mutation exposes latent DNA sequence-specific chromatin remodeling activity in FOXL2. FOXL2C134W-dependent chromatin remodeling activity redirected glucocorticoid receptor chromatin occupancy …

Antibody-Drug Conjugates Targeting The Egfr Ligand Epiregulin Elicit Robust Antitumor Activity In Colorectal Cancer, Joan Jacob, Yasuaki Anami, Peyton C High, Zhengdong Liang, Shraddha Subramanian, Sukhen C Ghosh, Solmaz Aghaamiri, Cara Guernsey-Biddle, Ha Tran, Julie Rowe, Ali Azhdarinia, Kyoji Tsuchikama, Kendra S Carmon

Faculty, Staff and Student Publications

As colorectal cancer remains a leading cause of cancer-related death, identifying therapeutic targets and approaches is essential to improve patient outcomes. The EGFR ligand epiregulin (EREG) is highly expressed in RAS wild-type (WT) and mutant colorectal cancer, with minimal expression in normal tissues, making it an attractive target for antibody-drug conjugate (ADC) development. In this study, we produced and purified an EREG mAb, H231, which had high specificity and affinity for human and mouse EREG. H231 also internalized to lysosomes, which is important for ADC payload release. ImmunoPET and ex vivo biodistribution studies showed significant tumor uptake of zirconium-89-labeled H231, …

Accumulation Of Cd38 In Hybrid Epithelial/Mesenchymal Cells Promotes Immune Remodeling And Metastasis In Breast Cancer, Tanvi H Visal, Recep Bayraktar, Petra Den Hollander, Michael A Attathikhun, Tieling Zhou, Jing Wang, Li Shen, Corina-Elena Minciuna, Meng Chen, Elizve Barrientos-Toro, Harsh Batra, Maria Gabriela Raso, Fei Yang, Edwin R Parra, Aysegul A Sahin, George A Calin, Sendurai A Mani

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC) is a highly metastatic subtype of breast cancer. The epithelial-to-mesenchymal transition is a nonbinary process in the metastatic cascade that generates tumor cells with both epithelial and mesenchymal traits known as hybrid EM cells. Recent studies have elucidated the enhanced metastatic potential of cancers featuring the hybrid EM phenotype, highlighting the need to uncover molecular drivers and targetable vulnerabilities of the hybrid EM state. Here, we discovered that hybrid EM breast tumors are enriched in CD38, an immunosuppressive molecule associated with worse clinical outcomes in liquid malignancies. Altering CD38 expression in tumor cell impacted migratory, invasive, …

Targeted Normoxemia And Supplemental Oxygen-Free Days In Critically Injured Adults: A Stepped-Wedge Cluster Randomized Clinical Trial, David J Douin, John D Rice, Erin L Anderson, Conner L Jackson, Alex C Cheng, Mengli Xiao, Jessica Cwik, Laurel E Beaty, Jessica L Wild, Mohamud R Daya, Pratik B Doshi, Shannon C Eastham, Michael D Goodman, Scott R Gunn, Jason S Haukoos, Jessica A Hudson, Jan O Jansen, Jason T Mcmullan, Julie A Rizzo, Martin A Schreiber, Wesley H Self, Matthew W Semler, Aimee Steinwand, Nicole Werner, Vikhyat S Bebarta, Steven G Schauer, Adit A Ginde

Faculty, Staff and Student Publications

Importance: Supplemental oxygen is fundamental to caring for critically injured adults but can expose them to excess inspired oxygen.

Objective: To determine the safety and effectiveness of targeting normoxemia in critically ill trauma patients.

Design, setting, and participants: This multicenter, stepped-wedge, cluster randomized clinical trial compared targeted normoxemia (defined as a peripheral oxygen saturation [Spo2] of 90% to 96%) with usual care among adult trauma patients admitted to an intensive care unit (ICU) at 8 level I trauma centers across the US. These trauma centers were randomized at 3-month intervals when they crossed over from usual care to targeting normoxemia. …

Somatic Acupressure For The Management Of The Fatigue-Sleep Disturbance-Depression Symptom Cluster In Breast Cancer Survivors: A Study Protocol For A Phase Iii Randomised Controlled Trial, Mengyuan Li, Tao Wang, Xian Liang Liu, Ren Li Deng, Wai Hang Kwok, Li Qun Yao, Jing Yu Benjamin Tan

Research outputs 2022 to 2026

Introduction The fatigue-sleep disturbance-depression symptom cluster (FSDSC) is commonly experienced by breast cancer (BC) survivors, leading to a deteriorated quality of life (QoL). Somatic acupressure (SA) has been recommended as a promising non-pharmacological intervention for cancer-related fatigue (the core symptom of the FSDSC) in the guidelines, showing its encouraging role in relieving cancer-related sleep disorders, fatigue and depression. This phase III randomised controlled trial (RCT) is designed to evaluate the effects, safety and cost-effectiveness of SA for managing the FSDSC in BC survivors. Methods This phase III RCT will be a partial-blinded, sham-controlled, three-arm, parallel clinical trial, involving a 7-week …

Evaluating The Effect Of Consumption Of Fermented Foods On Glycemic Control And Markers Of Cardiometabolic Risk Amongst Pre-Diabetic And Type 2 Diabetes Mellitus Adult Patients: A Systematic Review And Meta-Analysis, Alex Makau Muia

Master of Medicine in Family Medicine

Introduction 

Type 2 diabetes mellitus (T2DM) remains a major global health challenge, particularly in resource limited countries where conventional treatments are often inaccessible or unaffordable. While lifestyle interventions can reduce diabetes risk, their efficacy is moderate, highlighting the need for alternative strategies. Fermented foods (FFs), which are widely available and affordable, have been shown to improve glucose metabolism and may offer a promising adjunct in the prevention and management of T2DM and prediabetes.

Methods 

A systematic review and meta-analysis were conducted to assess the effects of fermented food consumption on glycemic control and cardiometabolic risk markers in adults with prediabetes …

A Preliminary Report Of The Carotenoid Assessment In Adults 50 Years Of Age And Older In Louisiana, Mary-Catherine Feazell

Master's Theses

Fruits and vegetables are at the core of a healthy, balanced diet. They assist in preventing the development of chronic diseases such as hypertension, diabetes, cardiovascular disease, and cancer (Fadnes, et al., 2022). Aging is a natural biological process followed by disease, cognitive impairment, and a natural decline of the body’s ability to perform at its best. The older adult population is currently the fastest-growing population globally (El-Shebiney et al., 2022). Vitamin A is crucial for several parts of the body to function correctly. Despite the positive effects of Vitamin A on the body, the recommended dietary intake is not …

The Efficacy Of The Minimally Invasive Lumbar Decompression (Mild®) Procedure: A Prisma-Compliant Systemic Review And Meta-Analysis, Xin-Yu Zhang, Jian-Li Zhao, Ya-Jing Wang, Jie Luan, Hong-Qi Lin, Dajie Wang

Department of Anesthesiology Faculty Papers

BACKGROUND: Lumbar spinal stenosis is the most common cause for spinal surgery of older adults. It is associated with pain in the legs and back as well as impaired ambulation. Minimally Invasive Lumbar Decompression (MILD®, Vertos Medical) is a percutaneous, image-guided lumbar decompression technique for central canal stenosis secondary to a hypertrophied ligamentum flavum. However, whether MILD can achieve adequate beneficial results in patients with lumbar spinal stenosis remains undetermined.

OBJECTIVE: To assess the efficacy and complications of MILD for lumbar spinal stenosis.

STUDY DESIGN: A systematic review and meta-analysis.

METHODS: Electronic databases were searched to identify all clinical trials …

Leveraging Artificial Intelligence And Machine Learning To Accelerate Discovery Of Disease-Modifying Therapies In Type 1 Diabetes., Melanie R. Shapiro, Erin M. Tallon, Matthew E. Brown, Amanda L. Posgai, Mark A. Clements, Todd M. Brusko

Manuscripts, Articles, Book Chapters and Other Papers

Progress in developing therapies for the maintenance of endogenous insulin secretion in, or the prevention of, type 1 diabetes has been hindered by limited animal models, the length and cost of clinical trials, difficulties in identifying individuals who will progress faster to a clinical diagnosis of type 1 diabetes, and heterogeneous clinical responses in intervention trials. Classic placebo-controlled intervention trials often include monotherapies, broad participant populations and extended follow-up periods focused on clinical endpoints. While this approach remains the 'gold standard' of clinical research, efforts are underway to implement new approaches harnessing the power of artificial intelligence and machine learning …

Massive Gastroduodenal Trichobezoar Removed With Hydrodissection: A Case Report, Seth Saylors, Cory Nonnemacher, Irene Isabel P. Lim

Manuscripts, Articles, Book Chapters and Other Papers

Introduction

Case presentation

Comparison Of The Use Of Therapeutic Plasma Exchange To Intravenous Immunoglobulin For Autoimmune Neurological Conditions At A Tertiary Hospital In Kenya., Swafiya Salim Busaidy

Master of Medicine in Internal Medicine

Background 

Plasma exchange (Barth et al.) and Intravenous Immunoglobulin (Barth et al.) have emerged as favored therapeutic options for autoimmune neurological conditions. Neurological conditions cause high morbidity and mortality in the sub-Saharan region. The utilization of these treatment options in Sub-Saharan Africa remains relatively unknown. We can determine the most efficient treatments with minimal cost implications by comparing the two treatment modalities in our setup.

Methods 

This retrospective descriptive chart review took place at Aga Khan University Hospital. It encompassed all patients admitted between 1st January 2011 and 31st December 2023 who had a neurological condition that necessitated treatment with …

Exploring Oxylipins In Host–Microbe Interactions And Their Impact On Infection And Immunity, Robert J. Neff, Christopher D. Radka

Markey Cancer Center Faculty Publications

Plasma lipids are essential components of biological systems, transported through interactions with proteins to maintain cellular functions. These lipids exist in various forms, such as fatty acids, glycerolipids, glycerophospholipids, sphingolipids, sterols, and prenol lipids, derived from dietary intake, adipose tissue, and biosynthesis. While the association between certain fatty acids and cardiovascular diseases has been widely recognized, polyunsaturated fatty acids (PUFAs) exhibit cardioprotective effects, reducing risks of arrhythmias and heart-related mortality. This is due to their role in the production of eicosanoids, which modulate inflammation. Chronic inflammation, particularly in obesity, is significantly influenced by fatty acids, with saturated fatty acids promoting …

Characterization, Performance, And Toxicological Assessment Of Polysulfone-Sulfonated Polyether Ether Ketone Membranes For Water Separation Applications, Muhammad Usman Yousaf, Lucca Madeo Cortarelli, Nerissa I. Jebet, Jason M. Unrine, Nirupam Aich, Olga V. Tsyusko, Isabel C. Escobar

Markey Cancer Center Faculty Publications

The removal of small molecular weight charged compounds from aqueous solutions using membrane remains a challenge. In this study, polysulfone (PSf)- and sulfonated polyether ether ketone (SPEEK)-based membranes were fabricated via non- solvent induced phase separation process (NIPS) using N-Methyl-2-Pyrrolidone (NMP) as solvent and water as non-solvent. Membranes were characterized structurally and morphologically, followed by toxicity assessment conducted before and after filtration, both with and without annealing at various pH values to evaluate potential leaching of trapped solvent from the membrane pores. Additionally, membrane performance was characterized using binary mixtures of cationic and anionic dyes. The results demonstrated selective filtration …

Computational Design And In Vitro And In Vivo Characterization Of An Apoe-Based Synthetic High-Density Lipoprotein For Sepsis Therapy, Ling Guo, Yaxia Yuan, Fang Zhang, Chang-Guo Zhan, Xiangan Li

Markey Cancer Center Faculty Publications

Introduction: Septic patients have low levels of high-density lipoproteins (HDLs), which is a risk factor. Replenishing HDLs with synthetic HDLs (sHDLs) has shown promise as a therapy for sepsis. This study aimed to develop a computational approach to design and test new types of sHDLs for sepsis treatment. Methods: We used a three-step computational approach to design sHDL nanoparticles based on the structure of HDLs and their binding to endotoxins. We tested the efficacy of these sHDLs in two sepsis mouse models—cecal ligation and puncture (CLP)-induced and P. aeruginosa-induced sepsis models—and assessed their impact on inflammatory signaling in cells. Results: …

Irisin-Mediated Muscle-Renal Crosstalk As A Protective Mechanism Against Contrast-Induced Acute Kidney Injury Via Cgas-Sting Signalling Inhibition, Long Peng, Suhua Li, Qiang Huang, Yuxiang Sun, Juan Sun, Ting Luo, Yanlin Wang, Zhaoyong Hu, Weiyan Lai, Hui Peng

Faculty, Staff and Students Publications

Background: Contrast-induced acute kidney injury (CI-AKI) continues to pose a pressing clinical challenge during invasive cardiovascular procedures due to the limited availability of preventative strategies. We aimed to demonstrate that irisin, a myokine induced by exercise, protects against CI-AKI by inhibiting the cGAS-STING inflammatory pathway.

Methods and results: We explored the relationship between serum irisin levels and CI-AKI incidence in patients administered the contrast media iohexol. Notably, lower serum irisin levels were strongly associated with an increased incidence of CI-AKI following contrast media administration. To establish a causal link between serum irisin levels and CI-AKI, we utilised a mouse model …

Exploration Of Cytokines And Microbiome Among Males And Females With Diarrhea-Predominant Irritable Bowel Syndrome, Li Juen Chen, Anna M Plantinga, Robert Burr, Kevin Cain, Pamela Barney, Tor Savidge, Robert J Shulman, Margaret Heitkemper, Kendra Kamp

Faculty, Staff and Students Publications

Background: Whether pathophysiological factors differ between males and females with irritable bowel syndrome-diarrhea (IBS-D) remains to be tested. To better understand potential sex differences, males with IBS-D were compared to naturally cycling females and to females with IBS-D taking hormonal contraception on plasma levels of cytokines and gut microbiome characteristics.

Methods: Males and females with Rome III IBS-D completed questionnaires and kept a daily symptom diary for 28 days. Blood and stool samples were collected between days 3 and 8 of the daily diary (estrogen-dominant days in naturally cycling females). Blood samples were analyzed for lipopolysaccharide (LPS)-stimulated and unstimulated cytokine …

Early Life Epigenetics And Childhood Outcomes: A Scoping Review, Srirupa Hari Gopal, Theresa Alenghat, Mohan Pammi

Faculty, Staff and Students Publications

Epigenetics is the study of changes in gene expression, without a change in the DNA sequence that are potentially heritable. Epigenetic mechanisms such as DNA methylation, histone modifications, and small non-coding RNA (sncRNA) changes have been studied in various childhood disorders. Causal links to maternal health and toxin exposures can introduce epigenetic modifications to the fetal DNA, which can be detected in the cord blood. Cord blood epigenetic modifications provide evidence of in-utero stressors and immediate postnatal changes, which can impact both short and long-term outcomes in children. The mechanisms of these epigenetic changes can be leveraged for prevention, early …

Icu Admission Prediction For Patients With Kawasaki Disease Or Mis-C Using Machine Learning., Jiwon Woo, Rebecca Mosier, Rishima Mukherjee, Ashraf S. Harahsheh, Supriya S. Jain, Geetha Raghuveer, Balasubramanian Sundaram, Simon Lee, Michael A. Portman, Nagib Dahdah, Marianna Fabi, Todd T. Nowlen, Audrey Dionne, Mona El Ganzoury, Tyler H. Harris, Benjamin T. Barnes, Frederic Dallaire, Paul Dancey, Kambiz Norozi, Mahmoud Alsalehi, Elif Seda Selamet Tierney, Jacqueline R. Szmuszkovicz, Pei-Ni Jone, Deepa Prasad, Anji T. Yetman, Nilanjana Misra, Mark D. Hicar, Deepika Thacker, Nadine F. Choueiter, Elisa Fernandez Cooke, Daniel Mauriello, Tapas Mondal, Matthew D. Elias, Kimberly E. Mchugh, Shae A. Merves, Luis Martin Garrido-Garcia, Michael Khoury, Guillermo Larios, Bhargava Chinni, Kaashvi Pruthi, Wenyu Yang, Joseph Greenstein, Casey Taylor, Pedrom Farid, Brian W. Mccrindle, Cedric Manlhiot, International Kawasaki Disease Registry

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease (KD) show a broad spectrum of clinical severity, from a relatively benign clinical course to requiring admission to the intensive care unit (ICU). With either, clinical deterioration may be rapid and unexpected.

OBJECTIVES: The aim of the study was to develop a machine learning (ML) model to predict future ICU admission for patients with KD or MIS-C to augment clinical decision-making.

METHODS: We developed a prediction model for ICU admission using 2,539 patientsfeatures, we developed predictive snapshot and window ML models with logistic regression, XGBoost, and random forest. Performance was …

Experiences Among Parents Caring For Children With Juvenile Idiopathic Arthritis At A Tertiary Referral Hospital In Kenya, Hassan Silim, Susan Wamithi, Roselyter Riang’A, Angela Migowa

Paediatrics and Child Health, East Africa

Background: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood. Despite the availability of effective treatment strategies such as disease-modifying antirheumatic drugs (DMARDs), JIA is reported to have a negative impact on the quality of life of the patients and their caregivers. Ascertaining the perceptions of the parents will help facilitate more effective management strategies and improve outcomes for these patients. This study aimed to ascertain parental experiences and perceptions of caring for children with juvenile idiopathic arthritis (JIA).

Methods: This was a single-center facility-based qualitative study. An in-depth interview guide was used to collect …

Functional Investigation Of A Putative Calcium-Binding Site Involved In The Inhibition Of Inositol 1,4, 5-Trisphosphate Receptor Activity, Vikas Arige, Larry E Wagner, Sundeep Malik, Mariah R Baker, Guizhen Fan, Irina I Serysheva, David I Yule

Faculty, Staff and Student Publications

The regulation of inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) activity is thought to define the spatiotemporal patterns of Ca2+ signals necessary for the appropriate activation of downstream effectors. The binding of both IP3 and Ca2+ is obligatory for IP3R channel opening. Ca2+ however regulates IP3R activity in a biphasic manner. Ca2+ binding to a high-affinity pocket formed by the third armadillo repeat domain and linker domain promotes IP3R channel opening without altering the Ca2+ dependency for channel inactivation. These data suggest that a distinct low-affinity Ca2+-binding site is responsible for the reduction in IP3R activity at higher [Ca2+]. We mutated a …

Safety And Efficacy Of Dtx401, An Aav8-Mediated Liver-Directed Gene Therapy, In Adults With Glycogen Storage Disease Type I A (Gsdia), David A Weinstein, Terry G Derks, David F Rodriguez-Buritica, Ayesha Ahmad, María-Luz Couce, John J Mitchell, Rebecca Riba-Wolman, Malaya Mount, Julieta Bonvin Sallago, Katalin M Ross, Melanie M Van Der Klauw, Foekje De Boer, Caroline Van Der Schaaf, Heather Saavedra, Miguel Martínez-Olmos, Elvis Atanga, Asad Hosseini, Deepali Mitragotri, Eric Crombez

Faculty, Staff and Student Publications

Glycogen storage disease type Ia (GSDIa) is a rare, life‐threatening, inherited carbohydrate metabolism disorder caused by glucose‐6‐phosphatase (G6Pase) deficiency, which is essential for glycogenolysis and gluconeogenesis. GSDIa management includes a strict medically prescribed diet that typically includes daily uncooked cornstarch doses, including overnight, to maintain euglycemia. DTX401 is an investigational adeno‐associated virus serotype 8 vector expressing the human G6PC1 gene that encodes G6Pase. This open‐label, phase 1/2, dose‐escalation, 52‐week gene therapy trial evaluated the safety and efficacy of a single DTX401 infusion in 12 adults with GSDIa (ClinicalTrials.gov Identifier: NCT03517085). Three participants in Cohort 1 received DTX401 2.0 × …

Diet-Enhanced Lrg1 Expression Promotes Insulin Hypersecretion And Er Stress In Pancreatic Beta Cells, Desirae D Morales, Jiyoon Ryu, Cong Wei, Jason T Hadley, Maia R Smith, Juli Bai, Juan C Lopez-Alvarenga, Srinivas Mummidi, Ravindranath Duggirala, Jane L Lynch, Feng Liu, Lily Q Dong

Faculty, Staff and Student Publications

Aims/hypothesis: Upregulation of serum leucine-rich α-2-glycoprotein 1 (LRG1) has been implicated in diet-induced obesity and metabolic disorders. However, its specific hormonal actions remain unclear. This study aimed to determine whether diet-enhanced serum LRG1 levels promote hyperinsulinaemia by directly stimulating insulin secretion from pancreatic beta cells.

Methods: Human serum samples were obtained from individuals (both male and female) undergoing plastic surgery. Male C57BL/6 wild-type and Lrg1 whole-body knockout (Lrg1KO) mice were fed a 45% high-fat diet, with serum samples collected every 2 weeks to monitor LRG1 and insulin levels throughout diet-induced obesity. MIN6 beta cells were used to investigate the effects …

Monte Carlo Modeling Of An Experimental Benchtop L-Shell X-Ray Fluorescence Imaging/Ct System Adopting Two Silicone Drift Detectors, Neerajan Nepal, Amrit Kaphle, Sandun Jayarathna, Sang Hyun Cho

Faculty, Staff and Student Publications

L-shell x-ray fluorescence (XRF) photons induced from gold nanoparticles (GNPs) after being irradiated by an x-ray beam allow for highly sensitive XRF imaging/computed tomography (XFCT) of biological samples containing GNPs at low concentrations on the order of parts-per-million (ppm). The primary goal of this Monte Carlo (MC) study was to investigate the feasibility of upgrading an existing experimental benchtop XRF/XFCT imaging setup adopting a single silicon drift detector (SDD), developed based on the aforementioned concept (often known as L-shell XFCT), by deploying another SDD within the same setup. Specifically, an MC model of the original single SDD L-shell XFCT setup, …

Proceedings Of The National Cancer Institute Workshop On Combining Immunotherapy With Radiotherapy: Challenges And Opportunities For Clinical Translation, Zachary S Morris, Sandra Demaria, Arta M Monjazeb, Silvia C Formenti, Ralph R Weichselbaum, James Welsh, Heiko Enderling, Jonathan D Schoenfeld, Joshua D Brody, Heather M Mcgee, Michele Mondini, Michael S Kent, Kristina H Young, Lorenzo Galluzzi, Sana D Karam, Willemijn S M E Theelen, Joe Y Chang, Mai Anh Huynh, Adi Daib, Sean Pitroda, Caroline Chung, Raphael Serre, Clemens Grassberger, Jie Deng, Quaovi H Sodji, Anthony T Nguyen, Ravi B Patel, Simone Krebs, Anusha Kalbasi, Caroline Kerr, Claire Vanpouille-Box, Logan Vick, Todd A Aguilera, Irene M Ong, Fernanda Herrera, Hari Menon, Deedee Smart, Jalal Ahmed, Robyn D Gartrell, Christina L Roland, Fatemeh Fekrmandi, Binita Chakraborty, Eric H Bent, Tracy J Berg, Alan Hutson, Samir Khleif, Andrew G Sikora, Lawrence Fong

Faculty, Staff and Student Publications

Radiotherapy both promotes and antagonises tumour immune recognition. Some clinical studies show improved patient outcomes when immunotherapies are integrated with radiotherapy. Safe, greater than additive, clinical response to the combination is limited to a subset of patients, however, and how radiotherapy can best be combined with immunotherapies remains unclear. The National Cancer Institute-Immuno-Oncology Translational Network-Society for Immunotherapy of Cancer-American Association of Immunology Workshop on Combining Immunotherapy with Radiotherapy was convened to identify and prioritise opportunities and challenges for radiotherapy and immunotherapy combinations. Sessions examined the immune effects of radiation, barriers to anti-tumour immune response, previous clinical trial data, immunological and …

Proteasome Augmentation Mitigates Age-Related Cognitive Decline In Mice, Danitra Parker, Kanisa Davidson, Pawel A Osmulski, Maria Gaczynska, Andrew M Pickering

Faculty, Staff and Student Publications

The aging brain experiences a significant decline in proteasome function. The proteasome is critical for many key neuronal functions including neuronal plasticity, and memory formation/retention. Treatment with proteasome inhibitors impairs these processes. Our study reveals a marked reduction in 20S and 26S proteasome activities in aged mice brains, including in the hippocampus, this is driven by reduced functionality of aged proteasome. The decline in proteasome activity is matched by a decline in 20S proteasome assembly. In contrast, 26S proteasome assembly was found to increase with age, though 26S proteasome activity was still found to decline. Our data suggests that age-related …

Qsp Modeling Shows Pathological Synergism Between Insulin Resistance And Amyloid-Beta Exposure In Upregulating Vcam1 Expression At The Bbb Endothelium, Zengtao Wang, Vaishnavi Veerareddy, Xiaojiao Tang, Kevin J Thompson, Sunil Krishnan, Krishna R Kalari, Karunya K Kandimalla

Faculty, Staff and Student Publications

Type 2 diabetes mellitus (T2DM), characterized by insulin resistance, is closely associated with Alzheimer's disease (AD). Cerebrovascular dysfunction is manifested in both T2DM and AD, and is often considered as a pathological link between the two diseases. Insulin signaling regulates critical functions of the blood-brain barrier (BBB), and endothelial insulin resistance could lead to BBB dysfunction, aggravating AD pathology. However, insulin signaling is intrinsically dynamic and involves interactions among numerous molecular mediators. Hence, a mechanistic systems biology model is needed to understand how insulin regulates BBB physiology and the consequences of its impairment in T2DM and AD. In this study, …

An Antibody-Toxin Conjugate Targeting Cd47 Linked To The Bacterial Toxin Listeriolysin O For Cancer Immunotherapy, Benjamin R Schrank, Yifan Wang, Annette Wu, Nhat Tran, Daeyong Lee, Jared Edwards, Kristin Huntoon, Shiyan Dong, Jonghoon Ha, Yifan Ma, Adam J Grippin, Seong Dong Jeong, Abin Antony, Mengyu Chang, Minjeong Kang, Thomas D Gallup, Albert C Koong, Jing Li, Kyuson Yun, Betty Y S Kim, Wen Jiang

Faculty, Staff and Student Publications

Antigen-presenting cells phagocytose tumor cells and subsequently cross-present tumor-derived antigens. However, these processes are impeded by phagocytosis checkpoints and inefficient cytosolic transport of antigenic peptides from phagolysosomes. Here, using a microbial-inspired strategy, we engineered an antibody-toxin conjugate (ATC) that targets the 'don't eat me' signal CD47 linked to the bacterial toxin listeriolysin O from the intracellular bacterium Listeria monocytogenes via a cleavable linker (CD47-LLO). CD47-LLO promotes cancer cell phagocytosis by macrophages followed by LLO release and activation to form pores on phagolysosomal membranes that enhance antigen cross-presentation of tumor-derived peptides and activate cytosolic immune sensors. CD47-LLO treatment in vivo significantly …

Seq-Scope: Repurposing Illumina Sequencing Flow Cells For High-Resolution Spatial Transcriptomics, Yongsung Kim, Weiqiu Cheng, Chun-Seok Cho, Yongha Hwang, Yichen Si, Anna Park, Mitchell Schrank, Jer-En Hsu, Angelo Anacleto, Jingyue Xi, Myungjin Kim, Ellen Pedersen, Olivia I Koues, Thomas Wilson, Changhee Lee, Goo Jun, Hyun Min Kang, Jun Hee Lee

Faculty, Staff and Student Publications

Spatial transcriptomics technologies aim to advance gene expression studies by profiling the entire transcriptome with intact spatial information from a single histological slide. However, the application of spatial transcriptomics is limited by low resolution, limited transcript coverage, complex procedures, poor scalability and high costs of initial setup and/or individual experiments. Seq-Scope repurposes the Illumina sequencing platform for high-resolution, high-content spatial transcriptome analysis, overcoming these limitations. It offers submicrometer resolution, high capture efficiency, rapid turnaround time and precise annotation of histopathology at a much lower cost than commercial alternatives. This protocol details the implementation of Seq-Scope with an Illumina NovaSeq 6000 …