Digital Commons Network^™

Circadian Immunity From Bench To Bedside: A Practical Guide, Huram Mok, Elaine Ostendorf, Alex Ganninger, Avi J. Adler, Guy Hazan, Jeffrey A. Haspel

2020-Current year OA Pubs

The immune system is built to counteract unpredictable threats, yet it relies on predictable cycles of activity to function properly. Daily rhythms in immune function are an expanding area of study, and many originate from a genetically based timekeeping mechanism known as the circadian clock. The challenge is how to harness these biological rhythms to improve medical interventions. Here, we review recent literature documenting how circadian clocks organize fundamental innate and adaptive immune activities, the immunologic consequences of circadian rhythm and sleep disruption, and persisting knowledge gaps in the field. We then consider the evidence linking circadian rhythms to vaccination, …

Current Understanding Of The Alzheimer's Disease-Associated Microbiome And Therapeutic Strategies, Dong-Oh Seo, David M Holtzman

2020-Current year OA Pubs

Alzheimer's disease (AD) is a fatal progressive neurodegenerative disease. Despite tremendous research efforts to understand this complex disease, the exact pathophysiology of the disease is not completely clear. Recently, anti-Aβ antibodies have been shown to remove amyloid from the brain and slow the clinical progression of mild dementia by ~30%. However, exploring alternative strategies is crucial to understanding and developing more effective therapeutic interventions. In recent years, the microbiota-gut-brain axis has received significant attention in the AD field. Numerous studies have suggested that alterations in the gut microbiota composition are associated with the progression of AD, and several underlying mechanisms …

Deep Learning-Based H-Score Quantification Of Immunohistochemistry-Stained Images, Zhuoyu Wen, Danni Luo, Shidan Wang, Ruichen Rong, Bret M Evers, Liwei Jia, Yisheng Fang, Elena V Daoud, Shengjie Yang, Zifan Gu, Emily N Arner, Cheryl M Lewis, Luisa M Solis Soto, Junya Fujimoto, Carmen Behrens, Ignacio I Wistuba, Donghan M Yang, Rolf A Brekken, Kathryn A O'Donnell, Yang Xie, Guanghua Xiao

Faculty, Staff and Student Publications

Immunohistochemistry (IHC) is a well-established and commonly used staining method for clinical diagnosis and biomedical research. In most IHC images, the target protein is conjugated with a specific antibody and stained using diaminobenzidine (DAB), resulting in a brown coloration, whereas hematoxylin serves as a blue counterstain for cell nuclei. The protein expression level is quantified through the H-score, calculated from DAB staining intensity within the target cell region. Traditionally, this process requires evaluation by 2 expert pathologists, which is both time consuming and subjective. To enhance the efficiency and accuracy of this process, we have developed an automatic algorithm for …

Immune Evasion, Infectivity, And Fusogenicity Of Sars-Cov-2 Ba286 And Flip Variants, Panke Qu, Kai Xu, Julia N Faraone, Negin Goodarzi, Yi-Min Zheng, Claire Carlin, Joseph S Bednash, Jeffrey C Horowitz, Rama K Mallampalli, Linda J Saif, Eugene M Oltz, Daniel Jones, Richard J Gumina, Shan-Lu Liu

Faculty, Staff and Student Publications

Evolution of SARS-CoV-2 requires the reassessment of current vaccine measures. Here, we characterized BA.2.86 and XBB-derived variant FLip by investigating their neutralization alongside D614G, BA.1, BA.2, BA.4/5, XBB.1.5, and EG.5.1 by sera from 3-dose-vaccinated and bivalent-vaccinated healthcare workers, XBB.1.5-wave-infected first responders, and monoclonal antibody (mAb) S309. We assessed the biology of the variant spikes by measuring viral infectivity and membrane fusogenicity. BA.2.86 is less immune evasive compared to FLip and other XBB variants, consistent with antigenic distances. Importantly, distinct from XBB variants, mAb S309 was unable to neutralize BA.2.86, likely due to a D339H mutation based on modeling. BA.2.86 had …

Metabolism, Fibrosis, And Apoptosis: The Effect Of Lipids And Their Derivatives On Keloid Formation, Chen-Yu Li, Ru-Xin Xie, Shi-Wei Zhang, Jiao Yun, Ai Zhong, Ying Cen, Jun-Jie Chen

Faculty, Staff and Student Publications

Keloids, pathological scars resulting from skin trauma, have traditionally posed significant clinical management challenges due to their persistence and high recurrence rates. Our research elucidates the pivotal roles of lipids and their derivatives in keloid development, driven by underlying mechanisms of abnormal cell proliferation, apoptosis, and extracellular matrix deposition. Key findings suggest that abnormalities in arachidonic acid (AA) synthesis and non-essential fatty acid synthesis are integral to keloid formation. Further, a complex interplay exists between lipid derivatives, notably butyric acid (BA), prostaglandin E2 (PGE2), prostaglandin D2 (PGD2), and the regulation of hyperfibrosis. Additionally, combinations of docosahexaenoic acid (DHA) with BA …

Parental Age Effects And Rett Syndrome, Xiaolan Fang, Lauren M Baggett, Raymond C Caylor, Alan K Percy, Jeffrey L Neul, Jane B Lane, Daniel G Glaze, Tim A Benke, Eric D Marsh, Kathleen J Motil, Judy O Barrish, Fran E Annese, Steven A Skinner

Children’s Nutrition Research Center Staff Publications

Rett syndrome (RTT) is a progressive neurodevelopmental disorder, and pathogenic Methyl-CpG-binding Protein 2 (MECP2) variants are identified in >95% of individuals with typical RTT. Most of RTT-causing variants in MECP2 are de novo and usually on the paternally inherited X chromosome. While paternal age has been reported to be associated with increased risk of genetic disorders, it is unknown whether parental age contributes to the risk of the development of RTT. Clinical data including parental age, RTT diagnostic status, and clinical severity are collected from 1226 participants with RTT and confirmed MECP2 variants. Statistical analyses are performed using Student t-test, …

Patient Interest In Exploring Nonsurgical Treatment Approaches For Early-Stage Breast Cancer: A Qualitative Study, Maya Guhan, Stacey M Crane, Lillian S Valerius, Denise De La Cruz, Benjamin D Smith, Wendy A Woodward, Melissa P Mitchell, Vicente Valero, Gaiane M Rauch, Savitri Krishnamurthy, Carla L Warnecke, Henry M Kuerer, Simona F Shaitelman

Faculty, Staff and Student Publications

Purpose: Advances in radiation therapy have enabled the ability to deliver ablative treatments, but there has been limited application of these treatments to early-stage breast cancers with a goal of omitting surgery. The purpose of this study was to explore patient interest in pursuing nonsurgical treatment approaches for their early-stage breast cancer.

Methods and materials: We conducted a qualitative study involving interviews with 21 patients with early-stage breast cancer who were eligible for participation in a phase 2 clinical trial offering omission of definitive surgery. Interviews were transcribed and an inductive, thematic analysis was performed by 3 independent reviewers to …

Absence Of Btk, Bcl2, And Plcg2 Mutations In Chronic Lymphocytic Leukemia Relapsing After First-Line Treatment With Fixed-Duration Ibrutinib Plus Venetoclax, Nitin Jain, Lisa J Croner, John N Allan, Tanya Siddiqi, Alessandra Tedeschi, Xavier C Badoux, Karl Eckert, Leo W K Cheung, Anwesha Mukherjee, James P Dean, Edith Szafer-Glusman, John F Seymour

Faculty, Staff and Student Publications

Purpose: Mutations in BTK, PLCG2, and BCL2 have been reported in patients with progressive disease (PD) on continuous single-agent BTK or BCL2 inhibitor treatment. We tested for these mutations in samples from patients with PD after completion of first-line treatment with fixed-duration ibrutinib plus venetoclax for chronic lymphocytic leukemia (CLL) in the phase II CAPTIVATE study.

Patients and methods: A total of 191 patients completed fixed-duration ibrutinib plus venetoclax (three cycles of ibrutinib then 12-13 cycles of ibrutinib plus venetoclax). Genomic risk features [del(11q), del(13q), del(17p), trisomy 12, complex karyotype, unmutated IGHV, TP53 mutated] and mutations in genes recurrently mutated …

Girth-Based Administered Activity For Pediatric 99mtc-Dmsa Spect, Ye Li, Justin L Brown, Jingyan Xu, Junyu Chen, Michael Ghaly, Monet Dugan, Xinhua Cao, Yong Du, Frederic H Fahey, Wesley Bolch, George Sgouros, Eric C Frey

Faculty, Staff and Student Publications

Background: Pediatric molecular imaging requires a balance between administering an activity that will yield sufficient diagnostic image quality while maintaining patient radiation exposure at acceptable levels. In current clinical practice, this balance is arrived at by the current North American Consensus Guidelines in which patient weight is used to recommend the administered activity (AA).

Purpose: We have previously demonstrated that girth (waist circumference at the level of the kidneys) is better at equalizing image quality than patient weight for pediatric Tc-99m DMSA renal function imaging. However, the correlation between image quality (IQ), AA, and patient girth has not been rigorously …

Convergent Mapk Pathway Alterations Mediate Acquired Resistance To Fgfr Inhibitors In Fgfr2 Fusion-Positive Cholangiocarcinoma, Timothy P Diperi, Ming Zhao, Kurt W Evans, Kaushik Varadarajan, Tyler Moss, Stephen Scott, Michael P Kahle, Charnel C Byrnes, Huiqin Chen, Sunyoung S Lee, Abdel-Baset Halim, Hiroshi Hirai, Volker Wacheck, Lawrence N Kwong, Jordi Rodon, Milind Javle, Funda Meric-Bernstam

Faculty, Staff and Student Publications

Background & aims: There is a knowledge gap in understanding mechanisms of resistance to fibroblast growth factor receptor (FGFR) inhibitors (FGFRi) and a need for novel therapeutic strategies to overcome it. We investigated mechanisms of acquired resistance to FGFRi in patients with FGFR2-fusion-positive cholangiocarcinoma (CCA).

Methods: A retrospective analysis of patients who received FGFRi therapy and underwent tumor and/or cell-free DNA analysis, before and after treatment, was performed. Longitudinal circulating tumor DNA samples from a cohort of patients in the phase I trial of futibatinib (NCT02052778) were assessed. FGFR2-BICC1 fusion cell lines were developed and secondary acquired resistance …

Rationale And Design Of The Nephrotic Syndrome Study Network (Neptune) Match In Glomerular Diseases: Designing The Right Trial For The Right Patient, Today, Howard Trachtman, Hailey Desmond, Amanda L Williams, Laura H Mariani, Sean Eddy, Wenjun Ju, Laura Barisoni, Heather K Ascani, Wendy R Uhlmann, Cathie Spino, Lawrence B Holzman, John R Sedor, Crystal Gadegbeku, Lalita Subramanian, Chrysta C Lienczewski, Tina Manieri, Scott J Roberts, Debbie S Gipson, Matthias Kretzler, Neptune Investigators

Faculty, Staff and Student Publications

Glomerular diseases are classified using a descriptive taxonomy that is not reflective of the heterogeneous underlying molecular drivers. This limits not only diagnostic and therapeutic patient management, but also impacts clinical trials evaluating targeted interventions. The Nephrotic Syndrome Study Network (NEPTUNE) is poised to address these challenges. The study has enrolled >850 pediatric and adult patients with proteinuric glomerular diseases who have contributed to deep clinical, histologic, genetic, and molecular profiles linked to long-term outcomes. The NEPTUNE Knowledge Network, comprising combined, multiscalar data sets, captures each participant's molecular disease processes at the time of kidney biopsy. In this editorial, we …

Intracranial Volume Is Driven By Both Genetics And Early Life Exposures: The Sol-Inca-Mri Study, Tamar Sofer, Einat Granot-Hershkovitz, Wassim Tarraf, Paola Filigrana, Carmen R Isasi, Shakira F Suglia, Robert Kaplan, Kent Taylor, Martha L Daviglus, Fernando D Testai, Donglin Zeng, Jianwen Cai, Myriam Fornage, Hector M González, Charles Decarli

Faculty, Staff and Student Publications

Intracranial volume (ICV) reflects maximal brain development and is associated with later-life cognitive abilities. We quantified ICV among first- and second-generation Hispanic and Latino adults from the Study of Latinos-Investigation of Cognitive Aging - MRI (SOL-INCA-MRI), estimated ICV heritability, and tested its associations with previously reported genetic variants, both individually and as a genetic risk score (GRS). We also estimated the association of ICV with early life environmental measures: nativity or age of immigration and parental education. The estimated heritability of ICV was 19% (95% CI, 0.1%-56%) in n=1781 unrelated SOL-INCA-MRI individuals. Four of 10 tested genetic variants were associated …

Drosophila Tweety Facilitates Autophagy To Regulate Mitochondrial Homeostasis And Bioenergetics In Glia, Ho Hang Leung, Christina Mansour, Morgan Rousseau, Anwar Nakhla, Kirill Kiselyov, Kartik Venkatachalam, Ching-On Wong

Faculty, Staff and Student Publications

Mitochondria support the energetic demands of the cells. Autophagic turnover of mitochondria serves as a critical pathway for mitochondrial homeostasis. It is unclear how bioenergetics and autophagy are functionally connected. Here, we identify an endolysosomal membrane protein that facilitates autophagy to regulate ATP production in glia. We determined that Drosophila tweety (tty) is highly expressed in glia and localized to endolysosomes. Diminished fusion between autophagosomes and endolysosomes in tty-deficient glia was rescued by expressing the human Tweety Homolog 1 (TTYH1). Loss of tty in glia attenuated mitochondrial turnover, elevated mitochondrial oxidative stress, and impaired locomotor functions. The cellular and organismal …

Multimorbidity Phenotypes In Ankylosing Spondylitis And Their Association With Disease Activity And Functional Impairment: Data From The Prospective Study Of Outcomes In Ankylosing Spondylitis Cohort, Paras Karmacharya, Cynthia S Crowson, Ryan J Lennon, Dilli Poudel, John M Davis, Alexis Ogdie, Jean W Liew, Michael M Ward, Mariko Ishimori, Michael H Weisman, Matthew A Brown, Mohammad H Rahbar, Mark C Hwang, John D Reveille, Lianne S Gensler

Faculty, Staff and Student Publications

Objectives: To examine the association of multimorbidity phenotypes at baseline with disease activity and functional status over time in ankylosing spondylitis (AS).

Methods: Patient-reported AS morbidities (comorbidities, N = 28 and extra-musculoskeletal manifestations, EMMs, N = 3) within 3 years of enrollment with a prevalence ≥1 %, were included from the Prospective Study of Outcomes in Ankylosing Spondylitis (PSOAS) cohort. We defined multimorbidity as ≥2 morbidities (MM2+) and substantial multimorbidity as ≥5 morbidities (MM5+). Multimorbidity clusters or phenotypes were identified using K-median clustering. Disease activity (ASDAS-CRP) and functional status (BASFI) measures were collected every 6 months. Generalized estimating equation method …

Phase 1/2 Trial Of Avelumab Combined With Utomilumab (4–1bb Agonist), Pf-04518600 (Ox40 Agonist), Or Radiotherapy In Patients With Advanced Gynecologic Malignancies, Anne Knisely, Jibran Ahmed, Bettzy Stephen, Sarina A Piha-Paul, Daniel Karp, Abdulrazzak Zarifa, Siqing Fu, David Sanghyun Hong, Jordi Rodon Ahnert, Timothy A Yap, Apostolia M Tsimberidou, Anas Alshawa, Ecaterina E Dumbrava, Yali Yang, Juhee Song, Funda Meric-Bernstam, Amir A Jazaeri, Aung Naing

Faculty, Staff and Student Publications

Background: Immune checkpoint blockade has shown mixed results in advanced/recurrent gynecologic malignancies. Efficacy may be improved through costimulation with OX40 and 4-1BB agonists. The authors sought to evaluate the safety and efficacy of avelumab combined with utomilumab (a 4-1BB agonist), PF-04518600 (an OX40 agonist), and radiotherapy in patients with recurrent gynecologic malignancies.

Methods: The primary end point in this six-arm, phase 1/2 trial was safety of the combination regimens. Secondary end points included the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors and immune-related Response Evaluation Criteria in Solid Tumors, the disease control rate (DCR), the …

Characteristics And Outcomes Of Patients With Multiple Myeloma Who Developed Therapy-Related Acute Myeloid Leukemia And Myelodysplastic Syndrome After Autologous Cell Transplantation, Fevzi F Yalniz, Uri Greenbaum, Oren Pasvolsky, Denái R Milton, Rashmi Kanagal-Shamanna, Jeremy Ramdial, Samer Srour, Rohtesh Mehta, Amin Alousi, Uday R Popat, Yago Nieto, Partow Kebriaei, Gheath Al-Atrash, Betul Oran, Chitra Hosing, Sairah Ahmed, Richard E Champlin, Elizabeth J Shpall, Muzaffar H Qazilbash, Qaiser Bashir

Faculty, Staff and Student Publications

Patients with multiple myeloma (MM) who undergo high-dose chemotherapy and autologous hematopoietic cell transplantation (Auto-HCT) have an increased risk of developing therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML). We retrospectively reviewed the medical records of all MM patients who underwent an Auto-HCT at our institution between 1 January and 31 December 2018 and later developed t-MDS/AML. Among the 2982 patients who underwent at least 1 Auto-HCT, 55 (2%) developed t-MDS/AML (MDS, n = 52; AML, n = 3). The median age at t-MDS/AML diagnosis was 66 years (range 43-83 years), and the median time from Auto-HCT to t-MDS/AML diagnosis …

Culturally Relevant Africultural Coping Moderates The Association Between Discrimination And Antiretroviral Adherence Among Sexual Minority Black Americans Living With Hiv., Glenn J. Wagner, Laura M. Bogart, David J. Klein, Sean J. Lawrence, Kathy Goggin, Mahlet Gizaw, Matt G. Mutchler

Manuscripts, Articles, Book Chapters and Other Papers

Exposure to discrimination has been linked to lower HIV antiretroviral therapy (ART) adherence and poor HIV care outcomes among Black Americans. Coping has been shown to mitigate the harmful effects of discrimination on health behaviors, but the use of cultural relevant Africultural coping strategies is understudied as a moderator of the association between intersectional discrimination and ART adherence among Black Americans. We used adjusted logistic regression to test whether Africultural coping strategies (cognitive/emotional debriefing; collective; spiritual-centered; ritual-centered) moderated associations between multiple forms of discrimination (HIV, sexual orientation, race) and good ART adherence (minimum of 75% or 85% of prescribed doses …

Circulating Tumor Dna And Radiological Tumor Volume Identify Patients At Risk For Relapse With Resected, Early-Stage Non-Small-Cell Lung Cancer, H T Tran, S Heeke, S Sujit, N Vokes, J Zhang, M Aminu, V K Lam, A Vaporciyan, S G Swisher, M C B Godoy, T Cascone, B Sepesi, D L Gibbons, J Wu, J V Heymach

Faculty, Staff and Student Publications

Background: Predicting relapse and overall survival (OS) in early-stage non-small-cell lung cancer (NSCLC) patients remains challenging. Therefore, we hypothesized that detection of circulating tumor DNA (ctDNA) can identify patients with increased risk of relapse and that integrating radiological tumor volume measurement along with ctDNA detectability improves prediction of outcome.

Patients and methods: We analyzed 366 serial plasma samples from 85 patients who underwent surgical resections and assessed ctDNA using a next-generation sequencing liquid biopsy assay, and measured tumor volume using a computed tomography-based three-dimensional annotation.

Results: Our results showed that patients with detectable ctDNA at baseline or after treatment and …

Enhancing Anti-Aml Activity Of Venetoclax By Isoflavone Me-344 Through Suppression Of Oxphos And/Or Purine Biosynthesis In Vitro, Katie H Hurrish, Yongwei Su, Shraddha Patel, Cassandra L Ramage, Jianlei Zhao, Brianna R Temby, Jenna L Carter, Holly Edwards, Steven A Buck, Sandra E Wiley, Maik Hüttemann, Lisa Polin, Juiwanna Kushner, Sijana H Dzinic, Kathryn White, Xun Bao, Jing Li, Jay Yang, Julie Boerner, Zhanjun Hou, Gheath Al-Atrash, Sergej N Konoplev, Jonathan Busquets, Stefano Tiziani, Larry H Matherly, Jeffrey W Taub, Marina Konopleva, Yubin Ge, Natalia Baran

Faculty, Staff and Student Publications

Venetoclax (VEN), in combination with low dose cytarabine (AraC) or a hypomethylating agent, is FDA approved to treat acute myeloid leukemia (AML) in patients who are over the age of 75 or cannot tolerate standard chemotherapy. Despite high response rates to these therapies, most patients succumb to the disease due to relapse and/or drug resistance, providing an unmet clinical need for novel therapies to improve AML patient survival. ME-344 is a potent isoflavone with demonstrated inhibitory activity toward oxidative phosphorylation (OXPHOS) and clinical activity in solid tumors. Given that OXPHOS inhibition enhances VEN antileukemic activity against AML, we hypothesized that …

Lfsproshiny: An Interactive R/Shiny App For Prediction And Visualization Of Cancer Risks In Families With Deleterious Germline Tp53 Mutations, Nam H Nguyen, Elissa B Dodd-Eaton, Gang Peng, Jessica L Corredor, Wenwei Jiao, Jacynda Woodman-Ross, Banu K Arun, Wenyi Wang

Faculty, Staff and Student Publications

Purpose: LFSPRO is an R library that implements risk prediction models for Li-Fraumeni syndrome (LFS), a genetic disorder characterized by deleterious germline mutations in the TP53 gene. To facilitate the use of these models in clinics, we developed LFSPROShiny, an interactive R/Shiny interface of LFSPRO that allows genetic counselors (GCs) to perform risk predictions without any programming components and further visualize the risk profiles of their patients to aid the decision-making process.

Methods: LFSPROShiny implements two models that have been validated on multiple LFS patient cohorts: a competing risk model that predicts cancer-specific risks for the first primary and a …

Gli1-Altered Mesenchymal Tumors With Actb Or Ptch1 Fusion: A Molecular And Clinicopathologic Analysis, Darcy A Kerr, Jeffrey M Cloutier, Matthew Margolis, Douglas A Mata, Nathalie J Rodrigues Simoes, William C Faquin, Dora Dias-Santagata, Shefali Chopra, Gregory W Charville, Sintawat Wangsiricharoen, Alexander J Lazar, Wei-Lien Wang, Andrew E Rosenberg, Julie Y Tse

Faculty, Staff and Student Publications

Mesenchymal tumors with GLI1 fusions or amplifications have recently emerged as a distinctive group of neoplasms. The terms GLI1-altered mesenchymal tumor or GLI1-altered soft tissue tumor serve as a nosological category, although the exact boundaries/criteria require further elucidation. We examined 16 tumors affecting predominantly adults (median age: 40 years), without sex predilection. Several patients had tumors of longstanding duration (>10 years). The most common primary site was soft tissue (n = 9); other sites included epidural tissue (n = 1), vertebra (n = 1), tongue (n = 1), hard palate (n = 1), and liver (n = 1). Histologically, …

Nci10066: A Phase 1/2 Study Of Olaparib In Combination With Ramucirumab In Previously Treated Metastatic Gastric And Gastroesophageal Junction Adenocarcinoma, Michael Cecchini, James M Cleary, Yu Shyr, Joseph Chao, Nataliya Uboha, May Cho, Anthony Shields, Shubham Pant, Laura Goff, Kristen Spencer, Edward Kim, Stacey Stein, Jeremy S Kortmansky, Sandra Canosa, Jeffrey Sklar, Elizabeth M Swisher, Marc Radke, Percy Ivy, Scott Boerner, Diane E Durecki, Chih-Yuan Hsu, Patricia Lorusso, Jill Lacy

Faculty, Staff and Student Publications

Background: Our preclinical work revealed tumour hypoxia induces homologous recombination deficiency (HRD), increasing sensitivity to Poly (ADP-ribose) polymerase inhibitors. We aimed to induce tumour hypoxia with ramucirumab thereby sensitising tumours to olaparib.

Patients and methods: This multi-institution single-arm Phase 1/2 trial enrolled patients with metastatic gastroesophageal adenocarcinoma refractory to ≥1 systemic treatment. In dose escalation, olaparib was evaluated at escalating dose levels with ramucirumab 8 mg/kg day 1 in 14-day cycles. The primary endpoint of Phase 1 was the recommended Phase 2 dose (RP2D), and in Phase 2 the primary endpoint was the overall response rate (ORR).

Results: Fifty-one patients …

Age-Associated Disparity In Phagocytic Clearance Affects The Efficacy Of Cancer Nanotherapeutics, Yifan Wang, Weiye Deng, Daeyong Lee, Long Yan, Yifei Lu, Shiyan Dong, Kristin Huntoon, Abin Antony, Xuefeng Li, Rui Ye, Yan Zhao, Feiyan Zhao, Benjamin R Schrank, Jonghoon Ha, Minjeong Kang, Mingming Yang, Ping Gong, Philip L Lorenzi, Lin Tan, Thomas D Gallup, Sarah K Tang, Zhaogang Yang, Jing Li, Nina N Sanford, Hongmei Wang, Betty Y S Kim, Wen Jiang

Faculty, Staff and Student Publications

Nanomedicines have been approved to treat multiple human diseases. However, clinical adoption of nanoformulated agents is often hindered by concerns about hepatic uptake and clearance, a process that is not fully understood. Here we show that the antitumour efficacy of cancer nanomedicine exhibits an age-associated disparity. Tumour delivery and treatment outcomes are superior in old versus young mice, probably due to an age-related decline in the ability of hepatic phagocytes to take up and remove nanoparticles. Transcriptomic- and protein-level analysis at the single-cell and bulk levels reveals an age-associated decrease in the numbers of hepatic macrophages that express the scavenger …

Activation Of Testosterone-Androgen Receptor Mediates Cerebrovascular Protection By Photobiomodulation Treatment In Photothrombosis-Induced Stroke Rats, Yu Feng, Zhihai Huang, Xiaohui Ma, Xuemei Zong, Celeste Yin-Chieh Wu, Reggie Hui-Chao Lee, Hung Wen Lin, Michael R Hamblin, Quanguang Zhang

Faculty, Staff and Student Publications

RATIONALE: Numerous epidemiological studies have reported a link between low testosterone levels and an increased risk of cerebrovascular disease in men. However, there is ongoing controversy surrounding testosterone replacement therapy due to potential side effects. PBMT has been demonstrated to improve cerebrovascular function and promote testosterone synthesis in peripheral tissues. Despite this, the molecular mechanisms that could connect PBMT with testosterone and vascular function in the brain of photothrombosis (PT)-induced stroke rats remain largely unknown.

METHODS: We measured behavioral performance, cerebral blood flow (CBF), vascular permeability, and the expression of vascular-associated and apoptotic proteins in PT-induced stroke rats treated with …

Glucose Metabolism In Posterior Cingulate Cortex Has Supplementary Value To Predict The Progression Of Cognitively Unimpaired To Dementia Due To Alzheimer’S Disease: An Exploratory Study Of 18f-Fdg-Pet, Qi Zhang, Chunqiu Fan, Luyao Wang, Taoran Li, Min Wang, Ying Han, Jiehui Jiang, Alzheimer’S Disease Neuroimaging Initiative

Faculty, Staff and Student Publications

Amyloid-β (Aβ) and tau are important biomarkers to predict the progression of cognitively unimpaired (CU) to dementia due to Alzheimer's disease (AD), according to the diagnosis framework from the US National Institute on Aging and the Alzheimer's Association (NIA-AA). However, it is clinically difficult to predict those subjects who were already with Aβ positive (A +) or tau positive (T +). As a typical characteristic of neurodegeneration in the diagnosis framework, the hypometabolism of the posterior cingulate cortex (PCC) has significant clinical value in the early prediction and prevention of AD. In this paper, we proposed the glucose metabolism in …

Concentrations Of Lead And Arsenic In Mother's Milk And Children's Blood In Peruvian Breastfeeding Dyads., Ana Maria Linares, Amanda Thaxton-Wiggins, Jason M Unrine

Nursing Faculty Publications

BACKGROUND: Toxic trace elements could enter human milk through mothers' food consumption, drinking water, air, or incidental soil ingestion, and are of concern to the nursing infant.

RESEARCH AIM: To determine the concentration of toxic trace elements (lead and arsenic) in Peruvian mothers' milk and their association with blood concentrations in their own infants 3-20 months old.

METHOD: This exploratory, cross-sectional study, carried out in Peru, included breastfeeding mother/child dyads (N = 40). Following standardized protocols, biospecimens of human milk and child's blood were collected.

RESULTS: Lead and arsenic concentrations in milk were above the method detection limits in …

Locoregional Therapies In Immunologically "Cold" Tumors: Opportunities And Clinical Trial Design Considerations, Pavlos Msaouel, Rahul A Sheth

Faculty, Staff and Student Publications

Immunotherapy has revolutionized cancer management, but many tumors, particularly immunologically "cold" tumors, remain resistant to the therapy. The combination of conventional systemic immunotherapies and locoregional interventional radiology approaches is being explored to transform these cold tumors into immunologically active "hot" ones. The present article uses the example of chromophobe renal cell carcinoma (ChRCC), a renal cell carcinoma subtype resistant to current systemic immunotherapies, to address practical and conceptual challenges that have prevented the activation of clinical trials specifically designed for this malignancy to date. The practical framework discussed herein can help overcome logistic and funding limitations and facilitate the development …

Tumor Treating Fields Increases Blood-Brain Barrier Permeability And Relative Cerebral Blood Volume In Patients With Glioblastoma, Michael Iv, Lewis Naya, Sajal Sanan, Samuel L Van Buskirk, Seema Nagpal, Reena P Thomas, Lawrence D Recht, Chirag B Patel

Faculty, Staff and Student Publications

BACKGROUND AND OBJECTIVE: 200 kHz tumor treating fields (TTFields) is clinically approved for newly-diagnosed glioblastoma (nGBM). Because its effects on conventional surveillance MRI brain scans are equivocal, we investigated its effects on perfusion MRI (pMRI) brain scans.

METHODS: Each patient underwent institutional standard pMRI: dynamic contrast-enhanced (DCE) and dynamic susceptibility contrast (DSC) pMRI at three time points: baseline, 2-, and 6-months on-adjuvant therapy. At each timepoint, the difference between T1 pre- versus post-contrast tumor volume (ΔT1) and these pMRI metrics were evaluated: normalized and standardized relative cerebral blood volume (nRCBV, sRCBV); fractional plasma volume (V

RESULTS: Among 13 pMRI datasets …

Mediators Of Necroptosis: From Cell Death To Metabolic Regulation, Xiaoqin Wu, Laura E Nagy, Jérémie Gautheron

Faculty, Staff and Student Publications

Necroptosis, a programmed cell death mechanism distinct from apoptosis, has garnered attention for its role in various pathological conditions. While initially recognized for its involvement in cell death, recent research has revealed that key necroptotic mediators, including receptor-interacting protein kinases (RIPKs) and mixed lineage kinase domain-like protein (MLKL), possess additional functions that go beyond inducing cell demise. These functions encompass influencing critical aspects of metabolic regulation, such as energy metabolism, glucose homeostasis, and lipid metabolism. Dysregulated necroptosis has been implicated in metabolic diseases, including obesity, diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD), contributing to chronic …

The Biology Of Hope: Inflammatory And Neuroendocrine Profiles In Ovarian Cancer Patients, Susan K Lutgendorf, Rachel M Telles, Brendan Whitney, Premal H Thaker, George M Slavich, Michael J Goodheart, Frank J Penedo, Alyssa E Noble, Steven W Cole, Anil K Sood, Benjamin W Corn

Faculty, Staff and Student Publications

INTRODUCTION: Although the concept of hope is highly relevant for cancer patients, little is known about its association with cancer-relevant biomarkers. Here we examined how hope was related to diurnal cortisol and interleukin-6 (IL-6), a pro-inflammatory cytokine previously associated with tumor biology and survival in ovarian cancer. Secondly, we examined whether hope and hopelessness are distinctly associated with these biomarkers.

METHOD: Participants were 292 high-grade ovarian cancer patients who completed surveys and provided saliva samples 4x/daily for 3 days pre-surgery to assess diurnal cortisol. Blood (pre-surgery) and ascites were assessed for IL-6. Hope and hopelessness were assessed using standardized survey …