Medicine and Health Sciences Commons^™

A Review Of Mirvetuximab Soravtansine-Gynx In Folate Receptor Alpha-Expressing Platinum-Resistant Ovarian Cancer, Judith A Smith, Patrick Medina, Mary Miao, Kathleen N Moore

Faculty, Staff and Student Publications

Purpose: To evaluate the pharmacology, efficacy, safety, and dosing and administration considerations (including adjusted ideal body weight [AIBW] dosing) for mirvetuximab soravtansine-gynx, a first-in-class folate receptor alpha (FRα)-directed antibody-drug conjugate for platinum-resistant ovarian cancer (PROC).

Summary: A literature search was conducted in PubMed using the terms "ovarian cancer" and "mirvetuximab soravtansine" of articles published from inception to April 16, 2024. Relevant publications, abstracts, and clinical trials were reviewed. Mirvetuximab soravtansine-gynx is dosed at 6 mg/kg AIBW every 3 weeks and comprises an FRα-binding antibody, a hydrophilic disulfide linker, and a maytansinoid DM4 payload. Mirvetuximab soravtansine-gynx binds to FRα, which induces …

Simultaneous Targeting Of Tumor Cells And Tumor-Associated Macrophages To Reprogram Glioblastoma Using Trypsinized Extracellular Vesicles Carrying Tumor Suppressive Microrna, Grace H Nguyen, Minhye Noh, Jin Muk Kang, Alexandra A Miller, Minxin Huang, Jiyeon Kim, Jeong-Yeon Lee, Sangwoon Chung, Hongyu Wang, George A Calin, Cynthia Ju, Holger K Eltzschig, Yeshavanth Banasavadi-Siddegowda, Zhongming Zhao, Ji Young Yoo, Tae Jin Lee

Faculty, Staff and Student Publications

Glioblastoma (GBM) remains difficult to treat due to poor drug delivery across the blood-brain barrier and an immunosuppressive tumor microenvironment (TME). Tumor-suppressive microRNAs (miRNAs) offer a promising strategy to reprogram both tumor cells and the TME, but inefficient delivery systems limit their clinical application. We previously reported that tumor-suppressive miR-138 regresses tumor growth in preclinical GBM models. Here, we demonstrate that trypsin digestion of extracellular vesicles (EVs) enhances labeling efficiency with folate (FA), enhancing selective targeting of folate receptor (FR)-positive GBM cells and enabling simultaneous targeting of tumor-associated macrophages (TAMs). FA-labeled trypsinized EVs (tEVs) loaded with miR-138 inhibit tumor growth, …

Identification Of Surrogate Biomarkers For Mucopolysaccharidosis Type Iva, Yasuhiko Ago, Shaukat Khan, Kimberly Klipner, Allison Bradford, Shunji Tomatsu

Department of Pediatrics Faculty Papers

Mucopolysaccharidosis type IVA (MPS IVA, Morquio A syndrome) is a rare inherited disorder characterized by skeletal dysplasia due to deficient N-acetylgalactosamine-6-sulfate sulfatase activity, resulting in glycosaminoglycan (GAG) accumulation. Identifying accurate biomarkers reflecting clinical severity and therapeutic response remains challenging. This study evaluated potential surrogate biomarkers, including N-terminal pro-C-type natriuretic peptide (NT-proCNP), collagen types I and II, mono-sulfated keratan sulfate (KS), di-sulfated KS, and chondroitin-6-sulfate (C6S), in blood and urine samples from 60 patients ranging from 1 to 62 years of age. NT-proCNP levels were significantly elevated in patients of all ages and negatively correlated with growth impairment, especially after 8 …

Turning Analysis Into Action: Opportunities And Challenges In Implementing Wastewater Science For Public Health Decision-Making, Anna Gitter, Valeria Ruvalcaba, Katelyn Clark, Theresa Tran Carapucci, Fuqing Wu, Blake M Hanson, Jennifer Deegan, John Balliew, Eric Boerwinkle, Anthony W Maresso, Kristina D Mena

Faculty, Staff and Students Publications

In the 5 years since the emergence of the COVID-19 pandemic, the field of wastewater-based epidemiology (WBE) has dramatically expanded with programs implemented across the globe to monitor for SARS-CoV-2 and other viruses of public health concern. However, the best way to use wastewater surveillance data and inform local communities of the utility of wastewater science remains limited and sporadically discussed. Specifically, there is vague guidance regarding interpreting varying levels of viral loads in wastewater for public health significance. While collaborative efforts are key to implementing these community-specific wastewater surveillance programs, effectively using the data for public health decision-making still …

Global Dna Methylation Differences Involving Germline Structural Variation Impact Gene Expression In Pediatric Brain Tumors, Fengju Chen, Yiqun Zhang, Wei Li, Fritz J Sedlazeck, Lanlan Shen, Chad J Creighton

Children’s Nutrition Research Center Staff Publications

The extent of genetic variation and its influence on gene expression across multiple tissue and cellular contexts is still being characterized, with germline Structural Variants (SVs) being historically understudied. DNA methylation also represents a component of normal germline variation across individuals. Here, we combine germline SVs (by short-read sequencing) with tumor DNA methylation across 1292 pediatric brain tumor patients. For thousands of methylation probes for CpG Islands (CGIs) or enhancers, rare and common SV breakpoints upstream or downstream associate with differential methylation in tumors spanning various histologic types, a significant subset involving genes with SV-associated differential expression. Cancer predisposition genes …

Ion-Dna Interactions As A Key Determinant Of Uracil Dna Glycosylase Activity., Sharon N Greenwood, Alexis N Dispensa, Matthew Wang, Justin R Bauer, Timothy D Vaden, Zhiwei Liu, Brian P Weiser

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Because of their ubiquitous presence, ions interact with numerous macromolecules in the cell and affect critical biological processes. Here, we discuss how cations including Mg²⁺ alter the enzymatic activity of a DNA glycosylase by tuning its affinity for DNA. The response of uracil DNA glycosylase (UNG2) to Mg²⁺ ions in solution is biphasic and paradoxical, where low concentrations of the ion stimulate the enzyme, but high concentrations inhibit the enzyme. We analyzed this phenomenon by modeling experimental data with a statistical framework that we empirically derived to understand molecular systems that display biphasic behaviors. Parameters from our statistical …

Towards Universal Chemosensory Testing: Needs, Barriers, And Opportunities, Steven D. Munger, Kai Zhao, Linda A. Barlow, Duncan Boak, Katie Boateng, Susan E. Coldwell, Pamela Dalton, Richard L. Doty, Jennifer E. Douglas, Valerie Duffy, Frank A. Franklin, John E. Hayes, Howard J. Hoffman, Patrice Hubert, Paule V. Joseph, Jeb M. Justice, Joshua M. Levy, Julie A. Mennella, Marianna Obrist, M. Yanina Pepino, Jayant M. Pinto, Edmund A. Pribitkin, Christopher T. Simons, Mark W. Albers, Valentina Parma

Department of Otolaryngology - Head and Neck Surgery Faculty Papers

Millions of people in the United States experience a reduced or distorted ability to smell or taste. Chemosensory disorders such as anosmia (the inability to smell), parosmia (distorted smell), or dysgeusia (altered taste) have major impacts on health and quality of life including difficulty sensing dangers such as fire or spoilage, a diminished palatability of food and drink that can negatively influence diet and nutrition, feelings of social isolation, and an increased incidence of frailty, anxiety, and depression. Smell or taste dysfunction can also be symptoms of other health issues, including sinonasal disease, cancer, or neurodegenerative disease. Aging adults are …

Patient-Reported Social Determinants Of Health In Patients With Heart Failure, Kenneth E Freedland, Brian C Steinmeyer, Judith A Skala, Robert M Carney, Michael W Rich

2020-Current year OA Pubs

BACKGROUND: Social determinants of health (SDOH) complicate medical care and affect clinical outcomes, but the lack of a reliable structured interview for medical patients has impeded clinical assessment and research on SDOH. We assessed the reliability and validity of a newly developed SDOH Patient Interview Form and investigated SDOH in patients with heart failure.

METHODS: The SDOH Patient Interview Form was administered to recently hospitalized patients with heart failure between January 2021 and April 2024. The interviews were recorded, and 50 were randomly selected for the interrater reliability analysis.

RESULTS: The sample included 367 participants (mean age, 61.2±12.1 years; 42.5% …

Histone Methyltransferase Ash1l Primes Metastases And Metabolic Reprogramming Of Macrophages In The Bone Niche, Chenling Meng, Kevin Lin, Wei Shi, Hongqi Teng, Xinhai Wan, Anna Debruine, Yin Wang, Xin Liang, Javier Leo, Feiyu Chen, Qianlin Gu, Jie Zhang, Vivien Van, Kiersten L Maldonado, Boyi Gan, Li Ma, Yue Lu, Di Zhao

Faculty, Staff and Student Publications

Bone metastasis is a major cause of cancer death; however, the epigenetic determinants driving this process remain elusive. Here, we report that histone methyltransferase ASH1L is genetically amplified and is required for bone metastasis in men with prostate cancer. ASH1L rewires histone methylations and cooperates with HIF-1α to induce pro-metastatic transcriptome in invading cancer cells, resulting in monocyte differentiation into lipid-associated macrophage (LA-TAM) and enhancing their pro-tumoral phenotype in the metastatic bone niche. We identified IGF-2 as a direct target of ASH1L/HIF-1α and mediates LA-TAMs' differentiation and phenotypic changes by reprogramming oxidative phosphorylation. Pharmacologic inhibition of the ASH1L-HIF-1α-macrophages axis elicits …

Rationale And Design Of The Repeat Trial: A Multicenter Randomized Trial Comparing Redo Surgical Aortic Valve Replacement To Valve-In-Valve Transcatheter Aortic Valve Replacement, Matthias Raschpichler, Suzanne De Waha, Stefan Blankenberg, Marcio A Diniz, Emilia Bagiella, Annetine C Gelijns, Vinicius F Calsavara, Aakriti Gupta, Niklas Schofer, Tsuyoshi Kaneko, Mohamed Abdel-Wahab, Holger Thiele, Raj Makkar, Michael A Borger

2020-Current year OA Pubs

BACKGROUND: Redo surgical aortic valve replacement (rSAVR) has for long been the therapeutic reference standard for degenerated surgical aortic bioprostheses. Valve-in-valve transcatheter aortic valve replacement (ViV-TAVR) has emerged as an alternative for patients at high surgical risk due to its lower invasiveness. The long-term clinical efficacy of ViV-TAVR in patients at low to intermediate surgical risk remains unknown.

METHODS AND RESULTS: To compare clinical outcomes of redo surgical aortic valve replacement versus ViV-TAVR in low- to intermediate-risk patients with degenerated surgical aortic bioprostheses. REPEAT (Repeat Intervention for Deteriorated Surgical Bioprosthetic Aortic Valves) is an investigator-initiated, international, multicenter, randomized, parallel, open-label …

Evaluation Of Knowledge, Attitudes And Vaccine Hesitancy Towards Mmr Vaccine Among Parents In The United Arab Emirates, Kamel A. Samara, Hiba Jawdat Barqawi, Deema M. Alhayali, Samah Mohamed Kannas, Rim M. Elmorsy, Eman Abu-Gharbieh

Abington Jefferson Health Papers

BACKGROUND: The Measles, Mumps, and Rubella (MMR) vaccine is highly effective, but vaccine hesitancy (VH) is a key barrier to achieving herd immunity. This study aims to assess the general attitudes and knowledge of UAE parents regarding measles and the MMR vaccine while identifying determinants of VH.

METHODOLOGY: A cross-sectional study was done from 15th April 2024 and 5th June 2024. This study recruited 462 parents residing in the UAE using convenience sampling. Recruitment occurred through various social media platforms including WhatsApp, X, and Instagram, as well as in public by approaching parents in parks and malls. Information collected included …

Epigenome-Wide Dna Methylation Association Study Of Chip Provides Insight Into Perturbed Gene Regulation, Sara Kirmani, Tianxiao Huan, Joseph C Van Amburg, Roby Joehanes, Md Mesbah Uddin, Ngoc Quynh H Nguyen, Bing Yu, Jennifer A Brody, Myriam Fornage, Jan Bressler, Nona Sotoodehnia, David A Ong, Fabio Puddu, James S Floyd, Christie M Ballantyne, Bruce M Psaty, Laura M Raffield, Pradeep Natarajan, Karen N Conneely, Joshua S Weinstock, April P Carson, Leslie A Lange, Kendra Ferrier, Nancy L Heard-Costa, Joanne Murabito, Alexander G Bick, Daniel Levy

Faculty, Staff and Student Publications

With age, hematopoietic stem cells can acquire somatic mutations in leukemogenic genes that confer a proliferative advantage in a phenomenon termed CHIP. How these mutations result in increased risk for numerous age-related diseases remains poorly understood. We conduct a multiracial meta-analysis of EWAS of CHIP in the Framingham Heart Study, Jackson Heart Study, Cardiovascular Health Study, and Atherosclerosis Risk in Communities cohorts (N = 8196) to elucidate the molecular mechanisms underlying CHIP and illuminate how these changes influence cardiovascular disease risk. We functionally validate the EWAS findings using human hematopoietic stem cell models of CHIP. We then use expression quantitative …

Effect Of Targeting Apoc-Iii With Plozasiran On Lipoprotein Particle Size And Number In Hypertriglyceridemia, Christie M Ballantyne, Daniel Gaudet, Robert S Rosenson, Robert A Hegele, Rong Zhou, Stacey Melquist, Jennifer Hellawell, Nicholas J Leeper

Faculty, Staff and Students Publications

Background: Plozasiran, an investigational siRNA targeting hepatic apoC-III, reduces triglyceride-rich lipoproteins (TRLs). The impact of plozasiran on lipoprotein particle numbers and sizes is unknown. However, reductions in the number of TRL particles (TRL-P) and a shift to possibly less atherogenic large low-density lipoprotein particles (LDL-P) are expected.

Objectives: This study aimed to determine the impact of plozasiran on lipoprotein particle concentration and subclass distribution using nuclear magnetic resonance (NMR) in 2 phase 2 studies.

Methods: Patients (N = 403) from SHASTA-2 (severe hypertriglyceridemia) and MUIR (mixed hyperlipidemia) were administered 2 total subcutaneous doses of plozasiran (10, 25, or 50 mg) …

Dietary Intake Of Protein By Food Source And Incident Hypertension Among Diverse Us Adults: The Mesa Study, Ji Yun Tark, Ruosha Li, Bing Yu, Alexis C Wood, Nikhil S Padhye, Marcia C De Oliveira Otto

Faculty, Staff and Student Publications

Background: Dietary guidelines recommend adequate protein intake from diverse sources for optimal blood pressure; however, its role in hypertension risk remains unclear. We examined prospective associations of protein intake and diversity, overall and by source, with hypertension risk in the MESA (Multi-Ethnic Study of Atherosclerosis) study.

Methods and results: Among 2294 participants aged 45 to 84 years without hypertension at baseline, total, animal, and plant protein intake was assessed using a 120-item food frequency questionnaire. Protein diversity was evaluated using count and the dissimilarity index. Over a 9-year median follow-up, 1356 hypertension cases were identified through blood pressure measurements and …

Sksr1 Identified As Key Virulence Factor In Cryptosporidium By Genetic Crossing, Wei He, Lianbei Sun, Tianyi Hou, Zuwei Yang, Fuxian Yang, Shengchen Zhang, Tianpeng Wang, Xinran Wang, Na Li, Yaqiong Guo, L David Sibley, Yaoyu Feng, Lihua Xiao

2020-Current year OA Pubs

Cryptosporidium is a major cause of severe diarrhea. Although Cryptosporidium isolates exhibit significant differences in infectivity and virulence, the genetic determinants for these traits are not clear. In this study, we use classical genetics to cross two Cryptosporidium parvum isolates of different virulence and use bulk segregant analysis of whole-genome sequences from the progeny to identify quantitative trait loci (QTL) associated with Cryptosporidium infectivity and virulence. Of the 23 genes in three QTL, two have loss-of-function mutations in the low-virulence isolates, including the SKSR1 gene encoding a variant secretory protein. Deletion of the SKSR1 gene or expression of the frame-shifted …

Approach To The Patient: From Endocrinopathy To The Diagnosis Of A Histiocytic Disorder, Polyzois Makras, Dana Erickson, Caroline J Davidge-Pitts, Eli L Diamond, Carl E Allen, Kenneth L Mcclain, Jithma P Abeykoon, Ronald S Go, Krishmita Siwakoti, Houman Sotoudeh, Aishwarya Ravindran, Lucinda M Gruber, Gaurav Goyal

Faculty, Staff and Students Publications

Endocrinopathies are frequently the initial presentation of histiocytic neoplasms, which are rare hematologic disorders affecting multiple organ systems. Langerhans cell histiocytosis and Erdheim-Chester disease are 2 such disorders known to infiltrate the hypothalamus and/or pituitary gland, leading to arginine vasopressin deficiency (AVP-D) and anterior pituitary dysfunction (APD) in 20% to 30% of cases, often as the first manifestation. Conversely, histiocytic disorders account for a notable proportion (10-15%) of all pituitary stalk lesions. The diagnosis of histiocytoses is often delayed in such cases due to the nonspecific presentation of endocrinopathies and pituitary involvement. Consequently, endocrinologists are at the frontline and uniquely …

E-Cigarette Or Vaping Product Use-Associated Lung Injury: A Comprehensive Review, Mohammad Asim Amjad, Daniel Ocazionez Trujillo, Rosa M Estrada-Y-Martin, Sujith V Cherian

Faculty, Staff and Student Publications

E-cigarette or vaping product use-associated lung injury (EVALI) is a critical and potentially fatal form of lung injury that gained considerable public health concern in 2019. The use of e-cigarettes and vaping products is causally associated with EVALI, a condition characterized by a constellation of respiratory symptoms, such as coughing, shortness of breath, and chest pain. This comprehensive narrative literature review explores the complexities of EVALI, including its association with the structure and composition of e-cigarettes and its epidemiology, pathogenesis, clinical and radiological manifestations, management strategies, and public health implications. Moreover, it uncovers the long-term repercussions of EVALI and underscores …

Neoadjuvant With Low-Dose Radiotherapy, Tislelizumab, Albumin-Bound Paclitaxel, And Cisplatin For Resectable Locally Advanced Head And Neck Squamous Cell Carcinoma: Phase Ii Single-Arm Trial, Zhigang Liu, Dong Wang, Guanjun Li, Muhua Yi, Zhaoyuan Zhang, Guihua Zhong, Liangfu Xu, Rong Jiang, Yannan Zheng, Linxuan Huang, Yingpeng Peng, Lizhong Liang, Jianpeng Li, Ye Liu, Jun Lai, Xianjuan Lv, Yongqiang Xu, Qiaodan Liu, Zhiqiang Wang, Zhutian Liu, Qinan Yang, Li Nie, Jiao Lei, Xiaotao Huang, Zhijie Liu, Wen Jiang

Faculty, Staff and Student Publications

Although pathological complete response (pCR) and major pathological response (MPR) rates of neoadjuvant immunotherapy combined with chemotherapy in head and neck squamous cell carcinoma (HNSCC) trials remain suboptimal, emerging evidence highlights the synergistic potential of combining low-dose radiotherapy with immunotherapy to promote the efficacy of immunotherapy. This phase II, open-label, single-arm, multicenter trial (NCT05343325) enrolled 28 patients with untreated stage III-IVB HNSCC (NeoRTPC02). Patients received neoadjuvant low-dose radiotherapy, the programmed death-1 (PD-1) inhibitor tislelizumab, albumin-bound paclitaxel, and cisplatin for two cycles, followed by radical resection ~4 weeks after treatment completion. The primary endpoint, pCR rate, was achieved in 14 of …

Functional Analysis Of Pathogenic Variants In Lamb1-Related Leukoencephalopathy Reveals Genotype-Phenotype Correlations And Suggests Its Role In Glial Cells, Rei Yasuda, Hirokazu Hashimoto, Mikiko Oka, Jung-Wan Mok, Marium Waqar, Brigitte Dauwalder, Oguz Kanca, Toshiki Mizuno, Shinya Yamamoto

Faculty, Staff and Students Publications

Laminin B1 (LAMB1) is one of the extracellular matrix (ECM) proteins that make up the basement membrane. Early frameshift, late frameshift, and missense variants in LAMB1 have been reported to cause rare monogenic neurological disorders that are collectively known as LAMB1-related leukoencephalopathy. Although there is some genotype-phenotype correlation, functional consequences of pathogenic LAMB1 variants are largely unknown. In this study, we aimed to elucidate function of the fly ortholog of this gene (LanB1) in the nervous system and to further study the functional consequences of the LAMB1 variants using Drosophila melanogaster. We found that the LanB1 gene is expressed on …

Tacrolimus Dosing In Liver Transplant Recipients Using Phenotypic Personalized Medicine: A Phase 2 Randomized Clinical Trial, Jeffrey Khong, Megan Lee, Curtis Warren, Un Kim, Sergio Duarte, Kenneth Andreoni, Sunaina Shrestha, Mark Johnson, Narendra Battula, Danielle Mckimmy, Thiago Beduschi, Ji-Hyun Lee, Derek Li, Chih-Ming Ho, Ali Zarrinpar

Department of Surgery Faculty Papers

Tacrolimus is the most commonly used immunosuppression drug after solid organ transplantation; however, its dosing is challenging due to substantial inter-individual variability, often resulting in blood levels that deviate from the target therapeutic range. We explored whether a dynamically customized, phenotypic-outcome-guided drug dosing method could improve maintenance of drug trough levels within pre-determined target ranges, focusing on tacrolimus immediately after liver transplantation. This single-center, partially blinded, completed clinical trial involved 62 adults undergoing liver transplantation, block randomized into parallel groups: standard-of-care (SOC) clinician-determined or Phenotypic Personalized Medicine (PPM)-guided tacrolimus dosing. The primary outcome was percentage of post-transplant days with large …

Science Tikkun: A Bioscience Pandemic Framework In A Hebrew Tradition Of Global Repair, Peter Hotez

Center for Medical Ethics and Health Policy Staff Publications

Over the past decade we have seen a steady increase in dangerous pandemic threats. They include two major Ebola epidemics and cholera in Africa; dengue, Zika, yellow fever in the Americas; a COVID-19 pandemic; and H5N1 in Texas. This is happening because of a confluence of modern forces including urbanization, deforestation, and climate change. Yet as pandemics emerge on a crowded and warming planet, anti-science disinformation and antisemitism impede our response. Science tikkun is an overarching framework for repair and redress. It honors the legacy of Maimonides, Teilhard de Chardin, and others who have sought reconciliation between science and religion.

St6galnac-I Regulates Tumor Cell Sialylation Via Nectin2/Muc5ac-Mediated Immunosuppression And Angiogenesis In Non-Small Cell Lung Cancer, Muthamil Iniyan Appadurai, Sanjib Chaudhary, Ashu Shah, Gopalakrishnan Natarajan, Zahraa W. Alsafwani, Parvez Khan, Dhananjay D. Shinde, Subodh M. Lele, Lynette M. Smith, Mohd W. Nasser, Surinder K. Batra, Apar Kishor Ganti, Imayavaramban Lakshmanan

Journal Articles: Biochemistry & Molecular Biology

Glycosylation controls immune evasion, tumor progression, and metastasis. However, how tumor cell sialylation regulates immune evasion remains poorly characterized. ST6GalNAc-I, a sialyltransferase that conjugates sialic acid to the glycans in glycoproteins, was overexpressed in an aggressive-type KPA (KrasG12D/+ Trp53R172H/+ Ad-Cre) lung adenocarcinoma (LUAD) model and patient samples. Proteomic and biochemical analysis indicated that ST6GalNAc-I mediated NECTIN2 sialylation in LUAD cells. ST6GalNAc-I-deficient tumor cells cocultured with T cells were more susceptible to T cell-mediated tumor cell killing, indicating a key role for NECTIN2 in T cell dysfunction. Mice injected with St6galnac-I-knockdown syngeneic cells showed reduced lung tumor incidence and Nectin2/Tigit-associated immunosuppression. …

Acute Kidney Injury Triggers Hypoxemia By Lung Intravascular Neutrophil Retention That Reduces Capillary Blood Flow, Yohei Komaru, Liang Ning, Carine Lama, Anusha Suresh, Eirini Kefaloyianni, Mark J. Miller, Shinichi Kawana, Hailey M Shepherd, Wenjun Li, Daniel Kreisel, Andreas Herrlich

2020-Current year OA Pubs

Sterile acute kidney injury (AKI) is common in the clinic and frequently associated with unexplained hypoxemia that does not improve with dialysis. AKI induces remote lung inflammation with neutrophil recruitment in mice and humans, but which cellular cues establish neutrophilic inflammation and how it contributes to hypoxemia is not known. Here we report that AKI induced rapid intravascular neutrophil retention in lung alveolar capillaries without extravasation into tissue or alveoli, causing hypoxemia by reducing lung capillary blood flow in the absence of substantial lung interstitial or alveolar edema. In contrast to direct ischemic lung injury, lung neutrophil recruitment during remote …

Label-Free Multimodal Optical Biopsy Reveals Biomolecular And Morphological Features Of Diabetic Kidney Tissue In 2d And 3d, Anthony A Fung, Zhi Li, Craig Boote, Petar Markov, Joseph P Gaut, Sanjay Jain, Lingyan Shi

2020-Current year OA Pubs

Kidney disease, the ninth leading cause of death in the United States, suffers from poor diagnostic efficiency (10%). Traditional biopsies use molecular reagents to enhance diagnostic power but are limited by overlapping spatial and chromatic signals, product quality variability, and additional processing. To address these challenges without disrupting routine diagnostics, we implement label-free imaging modalities-stimulated Raman scattering (SRS), second harmonic generation (SHG), and two-photon fluorescence (TPF)-within a single setup. We identify morphological, lipidomic, and metabolic biomarkers in control and diabetic kidney samples at subcellular resolution. Label-free Stimulated Raman Histology (SRH) reveals distinct collagen morphology, mesangial-glomerular volumes, lipid saturation, redox status, …

Modulation Of Her2 Internalization Enhances Single-Dose Antibody-Drug Potency In Her2+ Gastric Cancer, Abbey Zidel, Alex Benton, Emma Brown, Shayla Shmuel, Alex Vanover, Sandeep Surendra Panikar, Ron Bose, Haeseong Park, Andrew A Davis, Patrícia M R Pereira

2020-Current year OA Pubs

HER2 is a membrane receptor tyrosine kinase overexpressed in 18-20% of gastric tumors. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) that targets HER2-positive (HER2

Network Analysis Of The Cerebrospinal Fluid Proteome Reveals Shared And Unique Differences Between Sporadic And Familial Forms Of Amyotrophic Lateral Sclerosis, Adam N Trautwig, Cindy V Ly, Timothy M Miller, Et Al.

2020-Current year OA Pubs

BACKGROUND: Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease involving loss of motor neurons, typically results in death within 3-5 years of disease onset. Although roughly 10% of cases can be linked to a specific inherited mutation (e.g., C9orf72 hexanucleotide repeat expansion or SOD1 mutation), the cause(s) of most cases are unknown. Consequently, there is a critical need for biomarkers that reflect disease onset and progression across ALS subgroups.

METHODS: We employed tandem mass tag mass spectrometry (TMT-MS) based proteomics on cerebrospinal fluid (CSF) to identify and quantify 2105 proteins from sporadic, C9orf72, and SOD1 ALS patients, asymptomatic C9orf72 expansion carriers, …

Enhancing Theory-Driven Design And Evaluation Of Patient-Facing Technologies, Yang Gong, Yuheng Shi, Eric Yang, Katie Gahn, Heidi Mason, Yun Jiang

Faculty, Staff and Student Publications

Patient-facing technologies (PFTs) are essential tools for patient-centered outcome research. The current designs of PFTs need solid theoretical support and face challenges with maintenance and sustainability. This paper identifies PFT features and theoretical frameworks that support patient engagement in cancer care. Six prevailing PFT features - feedback & alert, a summary of entries, education materials, aggregated review, dedicated staff, and reminders - were identified in the primary literature, and five theoretical frameworks were adopted to guide the design and evaluation of 20 PFTs. Further research into user-centered design, personalization, and social context in PFT development is recommended to connect system …

Ubiquitin-Conjugating Enzyme Ube2n Modulates Proteostasis In Immunoproteasome-Positive Acute Myeloid Leukemia, Chiharu Ishikawa, Laura Barreyro, Avery M Sampson, Kathleen M Hueneman, Kwangmin Choi, Sophia Y Philbrook, Issac Choi, Lyndsey C Bolanos, Mark Wunderlich, Andrew G Volk, Stephanie S Watowich, Kenneth D Greis, Daniel T Starczynowski

Faculty, Staff and Student Publications

Altered protein homeostasis through proteasomal degradation of ubiquitinated proteins is a hallmark of many cancers. Ubiquitination, coordinated by E1, E2, and E3 enzymes, involves up to 40 E2-conjugating enzymes in humans to specify substrates and ubiquitin linkages. In a screen for E2 dependencies in acute myeloid leukemia (AML), ubiquitin conjugating enzyme E2 N (UBE2N) emerged as the top candidate. To investigate UBE2N's role in AML, we characterized an enzymatically defective mouse model of UBE2N, revealing UBE2N's requirement in AML without an impact on normal hematopoiesis. Unlike other E2s, which mediate lysine-48 (K48) polyubiquitination and degradation of proteins, UBE2N primarily synthesizes …

Development And Validation Of A Clinical Risk Model For Postoperative Outcome In Newly Diagnosed Glioblastoma: A Report Of The Rano Resect Group, Philipp Karschnia, Jacob S Young, Gilbert C Youssef, Antonio Dono, Levin Häni, Tommaso Sciortino, Francesco Bruno, Stephanie T Juenger, Nico Teske, Jorg Dietrich, Michael Weller, Michael A Vogelbaum, Martin Van Den Bent, Juergen Beck, Niklas Thon, Jasper K W Gerritsen, Shawn Hervey-Jumper, Daniel P Cahill, Susan M Chang, Roberta Rudà, Lorenzo Bello, Oliver Schnell, Yoshua Esquenazi, Maximilian I Ruge, Stefan J Grau, Raymond Y Huang, Patrick Y Wen, Mitchel S Berger, Annette M Molinaro, Joerg-Christian Tonn

Faculty, Staff and Student Publications

Background: Following surgery, patients with newly diagnosed glioblastoma frequently enter clinical trials. Nuanced risk assessment is warranted to reduce imbalances between study arms. Here, we aimed (I) to analyze the interactive effects of residual tumor with clinical and molecular factors on outcome and (II) to define a postoperative risk assessment tool.

Methods: The response assessment in neuro-oncology (RANO) resect group retrospectively compiled an international, seven-center training cohort of patients with newly diagnosed glioblastoma. The combined associations of residual tumor with molecular or clinical factors and survival were analyzed, and recursive partitioning analysis was performed for risk modeling. The resulting model …

Leveraging Data Pipeline And Llm To Advance Patient Safety Event Studies, Fagun Shah, Yue Yu, Yuheng Shi, Yang Gong

Faculty, Staff and Student Publications

Research utilizing the open-access MAUDE database frequently reveals unclear methodologies for extracting and processing medical device report (MDR) data, reducing reproducibility and consistency. By harnessing the OpenFDA API and our MAUDE extract-transform-load (ETL) pipeline that standardizes the extraction and transformation of MDR data, this project explores how a large language model (LLM) can be employed to analyze free-text narratives in MDRs, enhancing the accuracy and efficiency of event categorization. The ETL-LLM approach is demonstrated through MDRs related to endoscopic mucosal resection, with potential applications extending to other devices and patient issues. Additional efforts are necessary to expand the size and …