Digital Commons Network^™

Postoperative Caregiver Decision Regret Following Velopharyngeal Dysfunction Surgery., Rohit Nallani, Nathan Farrokhian, Meghan Tracy, Kevin J. Sykes, Jill M. Arganbright

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Decision regret (DR) is a powerful factor in medical decision-making, particularly for surgical decisions which carry multiple risks, impact quality of life (QOL), and have uncertain outcomes. While prior studies have investigated caregiver DR after tonsillectomy and otologic surgery, there is a paucity of data assessing DR following pediatric otolaryngology procedures. The aim of this study is to measure DR following velopharyngeal dysfunction (VPD) surgery.

METHODS: A cross-sectional survey study with chart review was performed of caregivers of children who had VPD surgery performed by a single surgeon at a tertiary children's hospital. Demographic, medical, and surgical history were …

Glutamatergic Regulation Of Mirna-Containing Intraluminal Vesicle Trafficking And Extracellular Vesicle Secretion From Cortical Neurons, Marcela Bertolio, Qiyi Li, Francesca E Mowry, Kathryn E Reynolds, Rashed Alananzeh, Haichao Wei, Kyoeun Keum, Rachel Jarvis, Jiaqian Wu, Yongjie Yang

Faculty, Staff and Student Publications

Neuronal extracellular vesicles (microvesicles and exosomes) are emerging secreted vesicular signals that play important roles in the CNS. Currently, little is known about how glutamatergic signalling affects the subcellular localisation of exosome precursor intraluminal vesicles (ILVs), microRNA (miR) packaging into ILVs and in vivo spreading of neuronal EVs. By selectively labelling ILVs and exosomes (but not plasma membrane-derived MVs) with GFP-tagged human CD63 (hCD63-GFP) in cortical neurons, we found that glutamate stimulation significantly redistributes subcellular localisation of hCD63-GFP+ ILVs, especially decreasing its co-localisation with multi-vesicular body (MVB) marker Rab7 while substantially promoting EV secretion. Interestingly, glutamate stimulation only modestly alters …

Time To Weight Plateau With Tirzepatide Treatment In The Surmount-1 And Surmount-4 Clinical Trials, Deborah B Horn, Scott Kahan, Rachel L Batterham, Dachuang Cao, Clare J Lee, Madhumita Murphy, Sylvia Gonsahn-Bollie, Farai Chigutsa, Adam Stefanski, Julia P Dunn

Faculty, Staff and Student Publications

The rate of weight reduction during obesity treatment declines over time and eventually reaches a weight plateau. We investigated factors associated with time to weight plateau (TTWP) in tirzepatide-treated participants with obesity or overweight in a post-hoc analysis of SURMOUNT-1 and SURMOUNT-4 trials. Participants adherent to tirzepatide treatment and achieving ≥5% weight loss by primary endpoint (week 72 SURMOUNT-1; week 88 SURMOUNT-4) were included. Weight plateau was defined as a weight change < 5% over a 12-week interval and all subsequent 12-week intervals. TTWP was time from randomization to the start of the first 12-week interval. Association between baseline characteristics and TTWP was assessed. Overall, 1438 participants in SURMOUNT-1 and 259 in SURMOUNT-4 were included. Across BMI categories (overweight, class I, II, and III), median TTWP in SURMOUNT-1 was 24.3, 26.0, 36.1, and 36.1 weeks, respectively (p < .05, class II and III vs. overweight). By week 72, 90.2%, 88.9%, 87.6%, and 87.8% of participants in SURMOUNT-1 had reached a weight plateau across respective BMI categories [Correction added on 22 January 2025, after first online publication: The "72%" has been changed to "72" in this version.]. Higher doses of tirzepatide (10/15 mg), younger age, and female sex were more likely to reach a weight plateau later. Results in SURMOUNT-4 were similar. In this post-hoc analysis, most participants reached a weight plateau by week 72. Higher doses of tirzepatide, younger age, and female sex were associated with a longer TTWP. Further research into modifiers of weight reduction phases with tirzepatide may inform treatment decisions for its use in chronic weight management. Clinical Trial Registration: ClinicalTrials.gov, identifiers NCT04184622 (SURMOUNT-1) and NCT04660643 (SURMOUNT-4), available at http://www.clinicaltrials.gov/.

An Enzyme-Linked Immunosorbent Assay (Elisa)-Based Activity Assay For Amp-Activated Protein Kinase (Ampk), Trezze P Nguyen, Shangze Lyu, Yang Liu

Faculty, Staff and Student Publications

AMP-activated protein kinase (AMPK) is the master regulator of cellular and organismal energy homeostasis, playing an essential role in modulating metabolism and other cellular processes. Substantial efforts have been made to develop pharmacological modulators of AMPK activity due to their therapeutic potential against various diseases. Measuring AMPK activity in vitro is a fundamental step for testing AMPK activators and inhibitors. Here, we report an enzyme-linked immunosorbent assay (ELISA)-based AMPK activity assay with simple steps and high sensitivity. This assay offers a robust, in-house alternative to the traditional radioactive methods and other approaches that rely on specialized reagents or commercial kits.

Emerging Technologies Of Single-Cell Multi-Omics, Yi June Kim, Koichi Takahashi

Faculty, Staff and Student Publications

The heterogeneity of the hematopoietic system was largely veiled by traditional bulk sequencing methods, which measure the averaged signals from mixed cellular populations. In contrast, single-cell sequencing has enabled the direct measurement of individual signals from each cell, significantly enhancing our ability to unveil such heterogeneity. Building on these advances, numerous single-cell multi-omics techniques have been developed into high-throughput, routinely accessible platforms, delineating the precise relationships among different layers of the central dogma in molecular biology. These technologies have uncovered the intricate landscape of genetic clonality and transcriptional heterogeneity in both normal and malignant hematopoietic systems, highlighting their roles in …

Outcomes After Palliative Radiation Therapy In Patients With Symptomatic Locoregionally Advanced Breast Cancer, Luisa E Jacomina, David M Swanson, Melissa P Mitchell, Wendy A Woodward, Benjamin D Smith, Karen E Hoffman, Chelain R Goodman, Haven R Garber, Susie X Sun, Timothy A Yap, Funda Meric-Bernstam, Isidora Y Arzu, Elizabeth S Bloom, Pamela J Schlembach, Eric A Strom, Michael C Stauder, Simona F Shaitelman

Faculty, Staff and Student Publications

Purpose: Symptomatic locoregionally advanced breast cancer (SLABC) can cause troublesome pain or wound complications that negatively impact quality of life. Although palliative radiation therapy (RT) can minimize tumor-related symptoms, how best to tailor RT to achieve the most meaningful and durable response is not well defined.

Methods and materials: This is a single institution, multi-site retrospective review of patients with SLABC treated between 2016 and 2023 with palliative RT to symptomatic disease in the breast, chest wall, and/or regional lymph node basins. Overall survival (OS), locoregional control (LC), clinical and radiographic treatment response, overall pain scores, and treatment-related toxicities were …

Egfr Controls Transcriptional And Metabolic Rewiring In Krasg12d Colorectal Cancer, Dana Krauß, Veronica Moreno-Viedma, Emi Adachi-Fernandez, Cristiano De Sá Fernandes, Jakob-Wendelin Genger, Ourania Fari, Bernadette Blauensteiner, Dominik Kirchhofer, Nikolina Bradaric, Valeriya Gushchina, Georgios Fotakis, Thomas Mohr, Ifat Abramovich, Inbal Mor, Martin Holcmann, Andreas Bergthaler, Arvand Haschemi, Zlatko Trajanoski, Juliane Winkler, Eyal Gottlieb, Maria Sibilia

Faculty, Staff and Student Publications

Inhibition of the epidermal growth factor receptor (EGFR) shows clinical benefit in metastatic colorectal cancer (CRC) patients, but KRAS-mutations are known to confer resistance. However, recent reports highlight EGFR as a crucial target to be co-inhibited with RAS inhibitors for effective treatment of KRAS mutant CRC. Here, we investigated the tumor cell-intrinsic contribution of EGFR in KRASG12D tumors by establishing murine CRC organoids with key CRC mutations (KRAS, APC, TP53) and inducible EGFR deletion. Metabolomic, transcriptomic, and scRNA-analyses revealed that EGFR deletion in KRAS-mutant organoids reduced their phenotypic heterogeneity and activated a distinct cancer-stem-cell/WNT signature associated with reduced cell size …

Association Of Sirt6 Expression With Risk Of Pneumonitis Induced By Radiotherapy In Cancer Patients, Fengyuan Yu, Zheng Gong, Yuan Li, Danial F Naseem, Chen Li, Miaowei Wen, Bingying Zhao, Zhezhe Xu, Shanshan Zhang, Rukun Zang, Ailu Wu, Qingxin Han, Shuhui Wu, Hongwei Li, Yipeng Song

Faculty, Staff and Student Publications

Thoracic tumours represent a significant proportion of malignant cancers. While radiotherapy (RT) improves prognosis, it can also lead to side effects such as radiation-induced pneumonitis (RP). Since SIRT6 is involved in DNA repair, energy metabolism and inflammation, this study aims to investigate the expression of SIRT6 in lymphocytes as a potential biomarker and therapeutic target for RP. This study included 170 patients diagnosed with thoracic tumours, all of whom underwent thoracic RT. RP was evaluated and classified as severe RP (SRP) and lower as non-severe RP (NSRP). Analyses were performed using SPSS version 26.0 and the R. Among 170 patients …

Clinical Interrogation Of Tp53 Aberrations And Its Impact On Survival In Patients With Myeloid Neoplasms, Jayastu Senapati, Sanam Loghavi, Guillermo Garcia-Manero, Guillin Tang, Tapan Kadia, Nicholas J Short, Hussein A Abbas, Naszrin Arani, Courtney D Dinardo, Gautam Borthakur, Naveen Pemmaraju, Betul Oran, Elizabeth Shpall, Uday Popat, Richard Champlin, Sherry Pierce, Sankalp Arora, Ghayas Issa, Musa Yilmaz, Keyur Patel, Koichi Takahashi, Guillermo Montalban-Bravo, Danielle Hammond, Fadi G Haddad, Farhad Ravandi, Hagop M Kantarjian, Naval G Daver

Faculty, Staff and Student Publications

In myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) with TP53 aberrations, dissecting the interaction amongst patient, disease and treatment factors are important for therapeutic decisions and prognostication. This retrospective analysis included patients with newly diagnosed MDS (>5% blasts) and AML with TP53 mutation(s) treated at MD Anderson Cancer Center. We factored patient age, TP53 aberration burden, therapy intensity and use of venetoclax in the AML subgroup, and allogeneic hematopoietic stem cell transplantation (HSCT) to interrogate outcomes. TP53 was annotated as high-risk (TP53HR) if >1 mutation, one mutation plus allelic deletion or a single mutation with variant allele frequency …

International Expert-Based Consensus Definition, Classification Criteria, And Minimum Data Elements For Osteoradionecrosis Of The Jaw: An Interdisciplinary Modified Delphi Study, Amy C Moreno, Erin E Watson, Laia Humbert-Vidan, Douglas E Peterson, Lisanne V Van Dijk, Teresa Guerrero Urbano, Lisa Van Den Bosch, Andrew J Hope, Matthew S Katz, Frank J P Hoebers, Ruth A Aponte Wesson, James E Bates, Paolo Bossi, Adeyinka F Dayo, Mélanie Doré, Eduardo Rodrigues Fregnani, Thomas J Galloway, Daphna Y Gelblum, Issa A Hanna, Christina E Henson, Sudarat Kiat-Amnuay, Anke Korfage, Nancy Y Lee, Carol M Lewis, Charlotte Duch Lynggaard, Antti A Mäkitie, Marco Magalhaes, Yvonne M Mowery, Carles Muñoz-Montplet, Jeffrey N Myers, Ester Orlandi, Jaymit Patel, Jillian M Rigert, Deborah Saunders, Jonathan D Schoenfeld, Ugur Selek, Efsun Somay, Vinita Takiar, Juliette Thariat, Gerda M Verduijn, Alessandro Villa, Nicholas S West, Max J H Witjes, Alex M Won, Mark E Wong, Christopher M K L Yao, Simon W Young, Kamal Al-Eryani, Carly E A Barbon, Doke J M Buurman, François J Dieleman, Theresa M Hofstede, Abdul Ahad Khan, Adegbenga O Otun, John C Robinson, Lauren Hum, Jorgen Johansen, Rajesh Lalla, Alexander Lin, Vinod Patel, Richard J Shaw, Mark S Chambers, Daniel Ma, Mabi Singh, Noam Yarom, Abdallah Sherif Radwan Mohamed, Katherine A Hutcheson, Stephen Y Lai, Clifton David Fuller

Faculty, Staff and Student Publications

Purpose: Osteoradionecrosis of the jaw (ORNJ) is a severe iatrogenic disease characterized by bone death after radiation therapy to the head and neck. With >9 published definitions and at least 16 classification systems, the true incidence and severity of ORNJ are obscured by lack of a standard for disease definition and severity assessment, leading to inaccurate estimation of incidence, reporting ambiguity, and likely underdiagnosis worldwide. This study aimed to achieve consensus on an explicit definition and phenotype of ORNJ and related precursor states through data standardization to facilitate effective diagnosis, monitoring, and multidisciplinary management of ORNJ.

Methods and materials: The …

An Enzyme-Linked Immunosorbent Assay (Elisa)-Based Activity Assay For Amp-Activated Protein Kinase (Ampk), Trezze P Nguyen, Shangze Lyu, Yang Liu

Faculty, Staff and Student Publications

AMP-activated protein kinase (AMPK) is the master regulator of cellular and organismal energy homeostasis, playing an essential role in modulating metabolism and other cellular processes. Substantial efforts have been made to develop pharmacological modulators of AMPK activity due to their therapeutic potential against various diseases. Measuring AMPK activity in vitro is a fundamental step for testing AMPK activators and inhibitors. Here, we report an enzyme-linked immunosorbent assay (ELISA)-based AMPK activity assay with simple steps and high sensitivity. This assay offers a robust, in-house alternative to the traditional radioactive methods and other approaches that rely on specialized reagents or commercial kits.

Targeted Sting Activation Using Modified Ultrasound-Responsive Microbubbles Enhances Immune Checkpoint Blockade Against Melanoma, Sina Khorsandi, Kristin Huntoon, Yifan Wang, Adam Woodward, Abin Antony, Connor Endsley, Nazia Hafeez, Jared L Edwards, Nicole Mccuen, Prasanna G Alluri, Betty Y S Kim, Wen Jiang, Jacques Lux

Faculty, Staff and Student Publications

Despite the recent successes of immune checkpoint inhibitors (ICIs) in treating advanced melanoma, durable clinical responses still remain limited. To boost immune responses, agents that target immune regulators, such as the Stimulator of Interferon Genes (STING) agonist cyclic GMP-AMP (cGAMP), are being investigated. However, their clinical translation is impeded by poor serum stability, rapid tissue clearance, and T-cell death due to off-target activation. Recently, a novel strategy termed Microbubble-assisted UltraSound-guided Immunotherapy of Cancer (MUSIC) has been reported to selectively deliver cGAMP directly into the cytosol of antigen-presenting cells with spatiotemporal control. The resulting activation of STING and downstream proinflammatory pathways …

Trem2 Depletion In Pancreatic Cancer Elicits Pathogenic Inflammation And Accelerates Tumor Progression Via Enriching Il-1Β+ Macrophages, Daowei Yang, Xinlei Sun, Hua Wang, Ignacio I Wistuba, Huamin Wang, Anirban Maitra, Yang Chen

Faculty, Staff and Student Publications

Background & aims: Pancreatic ductal adenocarcinoma (PDAC) has a complex tumor microenvironment enriched with tumor-associated macrophages. Triggering receptor expressed on myeloid cells 2 (TREM2) is highly expressed by a subset of macrophages in PDAC. However, the functional role of TREM2 in PDAC progression remains elusive.

Methods: We generated a novel transgenic mouse model (KPPC;Trem2-/-) that enables the genetic depletion of TREM2 in the context of spontaneous PDAC development. Single-cell RNA-sequencing analysis was used to identify changes in the tumor immune microenvironment on TREM2 depletion. We evaluated the impacts of TREM2 depletion on the tumor immune microenvironment to elucidate the functions …

Gsk-3484862, A Dnmt1 Degrader, Promotes Dnmt3b Expression In Lung Cancer Cells, Qin Chen, Swanand Hardikar, Kimie Kondo, Nan Dai, Ivan R Corrêa Jr, Meigen Yu, Marcos R Estecio, Xing Zhang, Taiping Chen, Xiaodong Cheng

Faculty, Staff and Student Publications

DNA methylation alterations, including hypermethylation and silencing of tumor suppressor genes, contribute to cancer formation and progression. The FDA-approved nucleoside analogs azacytidine and decitabine are effective demethylating agents for hematologic malignancies but their general use has been limited by their toxicity and ineffectiveness against solid tumors. GSK-3484862, a dicyanopyridine-containing, DNMT1-selective inhibitor and degrader, offers a promising lead for developing novel demethylating therapeutics. Here, we demonstrate that GSK-3484862 treatment upregulates DNMT3B expression in lung cancer cell lines (A549 and NCI-H1299). Disrupting DNMT3B in NCI-H1299 sensitizes these cells to GSK-3484862, enhancing its inhibitory effects on cell viability and growth. GSK-3484862 treatment induces …

Nlrp3 Inflammasome Activation Expands The Immunosuppressive Myeloid Stroma And Antagonizes The Therapeutic Benefit Of Sting Activation In Glioblastoma, Spencer T Lea, Chao-Hsien Chen, Jun Wei, Ivana William, Inés Lopez Del Castillo, Michael A Curran

Faculty, Staff and Student Publications

Glioblastoma (GBM) is the most common and deadly primary brain malignancy and is clinically refractory to immunotherapy. Active NLRP3 inflammasome signaling and IL-1β secretion have been observed in GBM, and NLRP3-driven myeloid-derived suppressor cell (MDSC) recruitment can mediate cancer immune evasion. Agonists of the cytosolic double-stranded DNA-sensing stimulator of IFN gene (STING) pathway can mediate proinflammatory conversion of cancer MDSCs; however, secretion of the NLRP3 products IL-1β and IL-18 has also been observed in certain myeloid populations following STING activation. In this study, we aimed to determine both the potential mechanistic synergy between STING and NLRP3 agonists, and the effects …

A Plain Language Summary Of Polaris: A Study To Look At Different Doses Of Encorafenib Plus Binimetinib For People With Braf V600-Mutant Melanoma With Brain Metastasis, Alexander M Menzies, Georgina V Long, Amiee Kohn, Hussein Tawbi, Jeffrey Webe, Keith Flaherty, Grant A Mcarthur, Paolo A Ascierto, Yanina Pfluger, Karl Lewis, Katy K Tsai, Omid Hamid, Hans Prenen, Luis Fein, Erjian Wang, Carolin Guenzel, Fan Zhang, Joseph F Kleh, Alessandra Di Pietro, Michael A Davies

Faculty, Staff and Student Publications

What is this summary about?People with a type of melanoma called advanced or metastatic BRAF V600- mutant melanoma, with a change in the BRAF gene, that has spread to the brain have poor outcomes.Current treatments include encorafenib (BRAFTOVI®) and binimetinib (MEKTOVI®). The POLARIS clinical study looked at whether increasing the encorafenib dose would make treatment more effective, with similar side effects, in these patients.The first part of the study, known as the safety lead-in, looked at the side effects of a high dose of encorafenib together with binimetinib. This was followed by a phase 2 part to …

Advancing The Development Of Trip13 Inhibitors: A High-Throughput Screening Approach, Rae M Sammons, Soma Ghosh, Lacin Yapindi, Eun Jeong Cho, Faye M Johnson, Kevin N Dalby

Faculty, Staff and Student Publications

TRIP13, a promising target for cancer therapy, has been identified as a key regulator of the mitotic checkpoint. Overexpression of TRIP13 is associated with poor clinical outcomes in various cancers. Inhibition of TRIP13 has the potential to address therapeutic challenges in cancer, particularly in therapy-resistant and Rb-deficient cancers. Despite the potential therapeutic benefits of TRIP13 inhibition, the development of TRIP13 inhibitors has been hindered by the lack of a robust high-throughput screening (HTS) assay. We developed a luminescence-based biochemical assay for TRIP13 activity to address this challenge using the ADP-Glo detection system. This assay offers high sensitivity, low background signal, …

Implications Of Omitting Sentinel Lymph Node Biopsy On Adjuvant Decision Making For Patients With Small Breast Cancers, Kerollos Nashat Wanis, Melissa P Mitchell, Sharon H Giordano, Jennifer Keating Litton, Simona F Shaitelman, Nina Tamirisa, Isabelle Bedrosian, Wenli Dong, Yu Shen, Kelly K Hunt, Puneet Singh, Susie X Sun, Abigail S Caudle, Henry M Kuerer, Funda Meric-Bernstam, Rosa F Hwang, Taiwo Adesoye

Faculty, Staff and Student Publications

Background: Selective omission of sentinel lymph node biopsy (SLNB) in patients with early breast cancer limits surgical morbidity. Adoption of this strategy relies on multidisciplinary consensus. Understanding how SLNB omission influences guideline-based adjuvant treatment decisions, and the proportion of patients impacted, can help guide decision-making.

Patients and methods: Data from the National Cancer Database (2018-2020) was used to estimate the proportions of patients with cT1N0 hormone receptor-positive breast cancer for whom adjuvant chemotherapy, CDK4/6 inhibitor therapy, and regional nodal irradiation decisions would be impacted by the absence of lymph node pathology if national treatment guidelines were followed. Because OncotypeDX score …

Therapeutic Hurdles In Acute Myeloid Leukemia: Leukemic Stem Cells, Inflammation And Immune Dysfunction, Bofei Wang, Patrick K Reville, Hussein A Abbas

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) is an aggressive and highly heterogeneous hematological malignancy characterized by clonal expansion and differentiation arrest in myeloid progenitor cells. Despite advancements in chemotherapy, allogeneic hematopoietic stem cell transplantation, and post-remission maintenance therapies, the long-term survival remains unsatisfactory with high rates of relapse and refractory. These therapeutic challenges are mediated by multiple factors, including the complexity of the cellular hierarchies in AML, the interaction of leukemic stem cells (LSCs) with the bone marrow niche, inflammation, and immune evasion mechanisms. Further, the absence of specific surface markers that distinguish LSCs from normal hematopoietic stem cells, together with LSCs' …

A Gut-On-A-Chip Incorporating Human Faecal Samples And Peristalsis Predicts Responses To Immune Checkpoint Inhibitors For Melanoma, Mattia Ballerini, Serena Galiè, Punit Tyagi, Carlotta Catozzi, Hariam Raji, Amir Nabinejad, Angeli D G Macandog, Alessandro Cordiale, Bianca Ionela Slivinschi, Karol K Kugiejko, Martina Freisa, Paola Occhetta, Jennifer A Wargo, Pier F Ferrucci, Emilia Cocorocchio, Nicola Segata, Andrea Vignati, Andrey Morgun, Michela Deleidi, Teresa Manzo, Marco Rasponi, Luigi Nezi

Faculty, Staff and Student Publications

Patient responses to immune checkpoint inhibitors can be influenced by the gastrointestinal microbiome. Mouse models can be used to study microbiome-host crosstalk, yet their utility is constrained by substantial anatomical, functional, immunological and microbial differences between mice and humans. Here we show that a gut-on-a-chip system mimicking the architecture and functionality of the human intestine by including faecal microbiome and peristaltic-like movements recapitulates microbiome-host interactions and predicts responses to immune checkpoint inhibitors in patients with melanoma. The system is composed of a vascular channel seeded with human microvascular endothelial cells and an intestinal channel with intestinal organoids derived from human …

Gut Microbiota In Immuno-Oncology: A Practical Guide For Medical Oncologists With A Focus On Antibiotics Stewardship, Arielle Elkrief, Bertrand Routy, Lisa Derosa, Laura Bolte, Jennifer A Wargo, Jennifer L Mcquade, Laurence Zitvogel

Faculty, Staff and Student Publications

The gut microbiota has emerged as a critical determinant of immune checkpoint inhibitor (ICI) efficacy, resistance, and toxicity. Retrospective and prospective studies profiling the taxonomic composition of intestinal microbes of patients treated with ICI have revealed specific gut microbial signatures associated with response. By contrast, dysbiosis, which can be caused by chronic inflammatory processes (such as cancer) or comedications, is a risk factor of resistance to ICI. Recent large-scale meta-analyses have confirmed that antibiotic (ATB) use before or during ICI therapy alters the microbiota repertoire and significantly shortens overall survival, even after adjusting for prognostic factors. These results underscore the …

Bispecific Antibodies In Hematologic And Solid Tumors: Current Landscape And Therapeutic Advances, Lorenzo Guidi, Julian Etessami, Carmine Valenza, Augusto Valdivia, Funda Meric-Bernstam, Enriqueta Felip, Giuseppe Curigliano

Faculty, Staff and Student Publications

Bispecific antibodies (bsAbs) have emerged as a novel class of therapeutics, offering a dual-targeting strategy to enhance the therapeutic efficacy of monoclonal antibodies, which is often limited by tumor heterogeneity and the occurrence of resistance mechanisms. By simultaneously engaging two distinct antigens or pathways, bsAbs disrupt multiple signaling cascades simultaneously, preventing escape mechanisms and offering a more durable response. Furthermore, they can optimize immune activation, improving immune cell recruitment strategies. In particular, T-cell engager bsAbs facilitate immune cell-mediated tumor destruction by linking T cells to tumor antigens. Instead, dual immune checkpoint inhibitors (CPIs) enhance immune activation by blocking inhibitory signals. …

Cll Cell-Derived Exosomes Alter The Immune And Hematopoietic Systems, Ivo Veletic, David M Harris, Uri Rozovski, Maria Teresa S Bertilaccio, George A Calin, Koichi Takahashi, Ping Li, Zhiming Liu, Taghi Manshouri, Rares-Constantin Drula, Ken Furudate, Muharrem Muftuoglu, Anwar Hossain, William G Wierda, Michael J Keating, Zeev Estrov

Faculty, Staff and Student Publications

The origins of immunosuppression, neutropenia, and anemia in patients with chronic lymphocytic leukemia (CLL) are not fully understood. Because in patients with CLL, circulating exosomes, which participate in cell-to-cell interactions, are CLL cell-derived, we examined whether those exosomes contribute to abnormal features of this disease. Our data revealed that CLL cell-derived exosomes engulfed by healthy donors’ monocytes, fibrocytes, and lymphocytes altered target-cell gene and protein expression and suppressed normal hematopoiesis. CLL cell-derived exosomes increased normal monocytes’ CD14 and CD16 expression such that it mimicked the accessory cell profile and upregulated T cells’ checkpoint PD-1 and CD160 protein levels, potentially reducing …

The Impact Of Nicu Death On Bereaved Mothers, Jennie Terranova

University Honors Theses

Infant loss in the United States occurs 5.6 per 1,000 live births. This paper examines risk factors that contribute to neonatal death. Prematurity is a risk factor for NICU admission. A portion of premature babies receiving care in the NICU will die. The stressful nature of the NICU has been studied widely in journals. The impact of NICU death on hospital staff and bereaved parents has been studied less. Mortality studies suggest that bereaved mothers are at a high risk of dying within the first 5 years after their child has died. Despite the frequency of maternal death post-child loss, …

Surveying Management Strategies For Pediatric Autoimmune Hepatitis, Lillie Baca

University Honors Theses

Pediatric autoimmune hepatitis (PAIH) is a long-term condition that requires ongoing treatment and regular monitoring. It is characterized by its elevation of liver enzymes, interface hepatitis, and the specific presence of circulating autoantibodies. There is a general lack of consensus on appropriate measures of diagnostic criteria, treatment medication, and beneficial practices for monitoring the disease. The existing literature contains several subtle discrepancies that challenge a practitioner's judgement for care management of children with autoimmune hepatitis. This study is a retrospective chart review aimed at understanding the current diagnostics, treatment, and long-term management strategies of PAIH at a single center. Also, …

Developmental Lead Exposure And Aggression In Male Rats: Influences Of Maternal Care And Environmental Enrichment, Shamaila Zafar, Courtney K. Williams, Jaehyun Joo, Blanca E. Himes, Jay S. Schneider

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Developmental lead (Pb) exposure results in a variety of cognitive deficits and behavioral issues including increased antisocial behavior and aggression. This study investigated the effect of developmental Pb exposure on aggression and violent behavior in male rats and the potential modulatory influences of quality of maternal care and enriched/non-enriched housing conditions. Long-Evans male rats with or without Pb exposure (perinatal or early postnatal) from low or high maternal care mothers (based on amounts of licking/grooming and arched- back nursing) were randomly assigned to live in enriched or non-enriched environments at weaning. At post- natal day 120–190, offensive aggression was assessed …

Neuroanatomical Features Of Naa10 And Naa15-Related Neurodevelopmental Syndromes, Rahi Patel, Rikhil Makwana, Carolina Christ, Elaine Marchi, Christina Y Miyake, Fabricio Guimaraes Goncalves, Gholson J Lyon, Matthew T Whitehead

Faculty, Staff and Students Publications

Background: NAA10-related and NAA15-related neurodevelopmental (ND) syndromes present with intellectual disability, hypotonia, cardiac abnormalities, and delayed development. While data exists on the clinical manifestations of these conditions, there are few reports describing the neuroanatomical abnormalities present on imaging.

Objective: We aim to provide neuroimaging analyses for a subset of probands with NAA10- and NAA15-related neurodevelopmental symptoms and assess the severity and number of neuroanatomical anomalies and their associated functional impairments to better understand the pathophysiology of these disease processes.

Materials and methods: Neuroimaging studies were obtained from 26 probands (18 with pathogenic variants in NAA10, 8 with pathogenic variants in …

Plasma Microbial Cell-Free Dna Sequencing For The Detection Of Kingella Kingae Pediatric Spinal Infections, Asim A Ahmed, Sarah Y Park, Matthew J Smollin, Martin S Lindner, Adriana Sarmiento Clemente, Ana Del Valle Penella, P Marcelo Laufer, Carolina Sanchez-Vegas, Manuel R Cotilla, Marian E Melish, Connie Trieu, Nazia A Kabani, Joshua Cooper, Audrey R Lloyd, David W Kimberlin, John C Arnold, Alejandro Jordan-Villegas, Lori E Patterson, Catherine E Foster, Pablo Yagupsky

Faculty, Staff and Students Publications

Background: Diagnosis of Kingella kingae skeletal system infections is made challenging by the microbe's fastidious nature. Detection and quantification of circulating microbial cell-free DNA (mcfDNA) in plasma by the Karius Test, a commercial metagenomic sequencing test, may offer promise in diagnosing pediatric spinal infections caused by difficult-to-culture organisms such as K. kingae .

Methods: Plasma mcfDNA sequencing detections of K. kingae from April 2018 to December 2020 were reviewed to identify pediatric (age < 18 years) patients. Medical charts of those with spinal infections were reviewed, and mcfDNA sequencing diagnostic performance was compared with usual care tests (ie, cultures, polymerase chain reaction).

Results: Ten children with K. kingae spinal infections were identified across 7 institutions. The median age was 16.5 months (range 11-23 months). All case-patients had vertebral osteomyelitis …

Linking Symptom Inventories Using Semantic Textual Similarity, Eamonn Kennedy, Shashank Vadlamani, Hannah M Lindsey, Kelly S Peterson, Kristen Dams O'Connor, Ronak Agarwal, Houshang H Amiri, Raeda K Andersen, Talin Babikian, David A Baron, Erin D Bigler, Karen Caeyenberghs, Lisa Delano-Wood, Seth G Disner, Ekaterina Dobryakova, Blessen C Eapen, Rachel M Edelstein, Carrie Esopenko, Helen M Genova, Elbert Geuze, Naomi J Goodrich-Hunsaker, Jordan Grafman, Asta K Håberg, Cooper B Hodges, Kristen R Hoskinson, Elizabeth S Hovenden, Andrei Irimia, Neda Jahanshad, Ruchira M Jha, Finian Keleher, Kimbra Kenney, Inga K Koerte, Spencer W Liebel, Abigail Livny, Marianne Løvstad, Sarah L Martindale, Jeffrey E Max, Andrew R Mayer, Timothy B Meier, Deleene S Menefee, Abdalla Z Mohamed, Stefania Mondello, Martin M Monti, Rajendra A Morey, Virginia Newcombe, Mary R Newsome, Alexander Olsen, Nicholas J Pastorek, Mary Jo Pugh, Adeel Razi, Jacob E Resch, Jared A Rowland, Kelly Russell, Nicholas P Ryan, Randall S Scheibel, Adam T Schmidt, Gershon Spitz, Jaclyn A Stephens, Assaf Tal, Leah D Talbert, Maria Carmela Tartaglia, Brian A Taylor, Sophia I Thomopoulos, Maya Troyanskaya, Eve M Valera, Harm Jan Van Der Horn, John D Van Horn, Ragini Verma, Benjamin S C Wade, Willian C Walker, Ashley L Ware, J Kent Werner, Keith Owen Yeates, Ross D Zafonte, Michael M Zeineh, Brandon Zielinski, Paul M Thompson, Frank G Hillary, David F Tate, Elisabeth A Wilde, Emily L Dennis

Faculty, Staff and Students Publications

An extensive library of symptom inventories has been developed over time to measure clinical symptoms of traumatic brain injury (TBI), but this variety has led to several long-standing issues. Most notably, results drawn from different settings and studies are not comparable. This creates a fundamental problem in TBI diagnostics and outcome prediction, namely that it is not possible to equate results drawn from distinct tools and symptom inventories. Here, we present an approach using semantic textual similarity (STS) to link symptoms and scores across previously incongruous symptom inventories by ranking item text similarities according to their conceptual likeness. We tested …

Psychometric Properties Of The Spanish Yale-Brown Obsessive-Compulsive Scale - Second Edition, Eric A Storch, Jessica Sc Cheng, Miranda Higham, Josselyn S Muñoz, Vanessa Zavala Cruz, Dayan Berrones, Diana P Obando, Jacey L Anderberg, Renee M Frederick, Vissente Tapia-Cuevas, Macarena Churruca Muñoz, Constanza Uribe Villar, Pablo R Moya, Marcos E Ochoa-Panaifo, Mayra C Martinez Mallen, Andrew D Wiese, Caitlin M Pinciotti, Melisa N Sagarnaga, Joseph F Mcguire, Ogechi C Onyeka, María B Moyano, Latin American Trans-Ancestry Initiative For Ocd Genomics (Latino), Brazilian Obsessive-Compulsive Spectrum Disorder Working Group (Gttoc), Wayne K Goodman, James J Crowley

Faculty, Staff and Students Publications

The Yale-Brown Obsessive-Compulsive Scale, Second Edition (Y-BOCS-II) is an evidence-based clinician-rated measure for assessing the presence and severity of obsessive-compulsive symptoms. The Spanish version of the Y-BOCS-II has not yet been validated. The present study examines the psychometric properties of the Spanish Y-BOCS-II (Spanish-Y-BOCS-II) in adults with obsessive-compulsive disorder (OCD) who are of Hispanic/Latino ancestry. The Spanish-Y-BOCS-II was administered to 1805 adults with OCD. Participants also completed a battery of measures assessing OCD, depression, and anxiety symptoms. The internal consistency for the Symptom Checklist (Kuder-Richardson-20=0.92), Obsession Severity (α=0.87), Compulsion Severity (α=0.86), and Total Severity (α=0.92) were high. The inter-rater reliability …