Browsing by Subject "Biomarkers"

Now showing 1 - 10 of 231
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    2016 Advances in Renal Imaging Symposium
    (Indiana University School of Medicine/IUPUI, 2016-11-15) IUPUI Imaging Research Symposium
    The primary objective of the “Advances in Renal Imaging” symposium is to provide a forum for nephrology researchers and imaging scientists to come together and discuss needed kidney imaging biomarkers and explore the development of imaging technologies designed to address specific renal imaging needs. The Symposium includes three sessions of oral presentations with invited speakers addressing the following general themes: 1) Need for advances in renal imaging and the identification of potential imaging biomarker targets; 2) Advances in renal microscopy methods for basic science renal research; 3) Advances in molecular, perfusion, and structural renal imaging.
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    2022 ACC Expert Consensus Decision Pathway on the Evaluation and Disposition of Acute Chest Pain in the Emergency Department: A Report of the American College of Cardiology Solution Set Oversight Committee
    (Elsevier, 2022) Kontos, Michael C.; de Lemos, James A.; Deitelzweig, Steven B.; Diercks, Deborah B.; Gore, M. Odette; Hess, Erik P.; McCarthy, Cian P.; McCord, James K.; Musey, Paul I., Jr.; Villines, Todd C.; Wright, Leesa J.; Emergency Medicine, School of Medicine
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    24435 Pathogen-specific metabolic pathways and innate immune responses associated with Chlamydia trachomatis infection and other STIs
    (Cambridge University Press, 2021) Ryan, John D.; Toh, Evelyn; Brothwell, Julie A.; Sun, Yuan; Jordan, Stephen J.; Nelson, David E.; Microbiology and Immunology, School of Medicine
    ABSTRACT IMPACT: This project seeks to identify unique host responses that are biomarkers for specific urethral pathogens, and which can be used in the development of point-of-care (POC) STI diagnostics. OBJECTIVES/GOALS: How Chlamydia trachomatis (CT) and other common STIs, e.g. Neisseria gonorrhoeae, evade immunity and elicit pathology in the male urethra is poorly understood. Our objective is to determine how STI-infected urethral epithelial cells, as well as the uninfected ‘bystander’ cells with which infected cells communicate, respond to CT and other STIs. METHODS/STUDY POPULATION: We evaluated how immortalized urethral cell lines - including transduced human urethral epithelial cells (THUECs) - respond to increasing doses of CT infectious particles using in vitro one-step progeny assays performed in the presence or absence of cycloheximide, a drug that inhibits eukaryotic protein synthesis. We will perform concurrent single-cell RNA sequencing (scRNA-seq) and multiplex cytokine analyses to determine how different CT doses impact the transcriptomes of infected and bystander urethral epithelial cells and modulate cytokine production of the overall monolayer. Results of these experiments will inform the feasibility of performing similar analyses in situ using urethral swabs from men with clinically diagnosed urethritis. RESULTS/ANTICIPATED RESULTS: Our results demonstrate that immune-competent urethral cell monolayers strongly resist CT infection, unless most of the cells are simultaneously infected. This suggests that uninfected bystander cells sense CT-infected cells and secrete soluble factors that may act to limit CT proliferation in infected cells and to inform remaining uninfected cells that a potential pathogen is present. We anticipate that our scRNA-seq and cytokine analyses will identify both specific effector pathways that protect against CT and intracellular signals that modulate them. We speculate that these pathways and signals may differ during infection with CT and other STIs. Importantly, we anticipate that our in vitro model of CT infection will be highly representative of in situ immune responses observed in urethras of infected men. DISCUSSION/SIGNIFICANCE OF FINDINGS: In men, common STIs including CT are usually managed syndromically due to a lack of POC diagnostics. By determining how STIs elicit urethral inflammation and identifying countermeasures that STIs use to evade urethral immunity, we can identify host responses that serve as biomarkers for urethritis, generally, and for specific urethral pathogens.
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    A Bayesian Phase I/II Design to Determine Subgroup-Specific Optimal Dose for Immunotherapy Sequentially Combined with Radiotherapy
    (Wiley, 2023) Guo, Beibei; Zang, Yong; Lin, Li-Hsiang; Zhang, Rui; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
    Sequential administration of immunotherapy following radiotherapy (immunoRT) has attracted much attention in cancer research. Due to its unique feature that radiotherapy upregulates the expression of a predictive biomarker for immunotherapy, novel clinical trial designs are needed for immunoRT to identify patient subgroups and the optimal dose for each subgroup. In this article, we propose a Bayesian phase I/II design for immunotherapy administered after standard-dose radiotherapy for this purpose. We construct a latent subgroup membership variable and model it as a function of the baseline and pre-post radiotherapy change in the predictive biomarker measurements. Conditional on the latent subgroup membership of each patient, we jointly model the continuous immune response and the binary efficacy outcome using plateau models, and model toxicity using the equivalent toxicity score approach to account for toxicity grades. During the trial, based on accumulating data, we continuously update model estimates and adaptively randomize patients to admissible doses. Simulation studies and an illustrative trial application show that our design has good operating characteristics in terms of identifying both patient subgroups and the optimal dose for each subgroup.
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    A discovery-based proteomics approach identifies protein disulphide isomerase (PDIA1) as a biomarker of β cell stress in type 1 diabetes
    (Elsevier, 2023) Syed, Farooq; Singhal, Divya; Raedschelders, Koen; Krishnan, Preethi; Bone, Robert N.; McLaughlin, Madeline R.; Van Eyk, Jennifer E.; Mirmira, Raghavendra G.; Yang, Mei-Ling; Mamula, Mark J.; Wu, Huanmei; Liu, Xiaowen; Evans-Molina, Carmella; Pediatrics, School of Medicine
    Background: Stress responses within the β cell have been linked with both increased β cell death and accelerated immune activation in type 1 diabetes (T1D). At present, information on the timing and scope of these responses as well as disease-related changes in islet β cell protein expression during T1D development is lacking. Methods: Data independent acquisition-mass spectrometry was performed on islets collected longitudinally from NOD mice and NOD-SCID mice rendered diabetic through T cell adoptive transfer. Findings: In islets collected from female NOD mice at 10, 12, and 14 weeks of age, we found a time-restricted upregulation of proteins involved in stress mitigation and maintenance of β cell function, followed by loss of expression of protective proteins that heralded diabetes onset. EIF2 signalling and the unfolded protein response, mTOR signalling, mitochondrial function, and oxidative phosphorylation were commonly modulated pathways in both NOD mice and NOD-SCID mice rendered acutely diabetic by T cell adoptive transfer. Protein disulphide isomerase A1 (PDIA1) was upregulated in NOD islets and pancreatic sections from human organ donors with autoantibody positivity or T1D. Moreover, PDIA1 plasma levels were increased in pre-diabetic NOD mice and in the serum of children with recent-onset T1D compared to non-diabetic controls. Interpretation: We identified a core set of modulated pathways across distinct mouse models of T1D and identified PDIA1 as a potential human biomarker of β cell stress in T1D.
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    A framework for translating tauopathy therapeutics: Drug discovery to clinical trials
    (Wiley, 2024) Feldman, Howard H.; Cummings, Jeffrey L.; Boxer, Adam L.; Staffaroni, Adam M.; Knopman, David S.; Sukoff Rizzo, Stacey J.; Territo, Paul R.; Arnold, Steven E.; Ballard, Clive; Beher, Dirk; Boeve, Bradley F.; Dacks, Penny A.; Diaz, Kristophe; Ewen, Colin; Fiske, Brian; Gonzalez, M. Isabel; Harris, Glenn A.; Hoffman, Beth J.; Martinez, Terina N.; McDade, Eric; Nisenbaum, Laura K.; Palma, Jose-Alberto; Quintana, Melanie; Rabinovici, Gil D.; Rohrer, Jonathan D.; Rosen, Howard J.; Troyer, Matthew D.; Kim, Doo Yeon; Tanzi, Rudolph E.; Zetterberg, Henrik; Ziogas, Nick K.; May, Patrick C.; Rommel, Amy; Medicine, School of Medicine
    The tauopathies are defined by pathological tau protein aggregates within a spectrum of clinically heterogeneous neurodegenerative diseases. The primary tauopathies meet the definition of rare diseases in the United States. There is no approved treatment for primary tauopathies. In this context, designing the most efficient development programs to translate promising targets and treatments from preclinical studies to early-phase clinical trials is vital. In September 2022, the Rainwater Charitable Foundation convened an international expert workshop focused on the translation of tauopathy therapeutics through early-phase trials. Our report on the workshop recommends a framework for principled drug development and a companion lexicon to facilitate communication focusing on reproducibility and achieving common elements. Topics include the selection of targets, drugs, biomarkers, participants, and study designs. The maturation of pharmacodynamic biomarkers to demonstrate target engagement and surrogate disease biomarkers is a crucial unmet need. HIGHLIGHTS: Experts provided a framework to translate therapeutics (discovery to clinical trials). Experts focused on the "5 Rights" (target, drug, biomarker, participants, trial). Current research on frontotemporal degeneration, progressive supranuclear palsy, and corticobasal syndrome therapeutics includes 32 trials (37% on biologics) Tau therapeutics are being tested in Alzheimer's disease; primary tauopathies have a large unmet need.
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    A phase I study of the anaplastic lymphoma kinase inhibitor ceritinib in combination with gemcitabine-based chemotherapy in patients with advanced solid tumors
    (Wiley, 2021) Fountzilas, Christos; Adjei, Alex; Opyrchal, Mateusz; Evans, Rachel; Ghasemi, Mohammad; Attwood, Kristopher; Groman, Adrienne; Bshara, Wiam; Goey, Andrew; Wilton, John; Ma, Wen Wee; Iyer, Renuka; Medicine, School of Medicine
    In this phase I, dose-escalation study, we sought to determine the maximum tolerated dose (MTD) of the anaplastic lymphoma kinase/c-ROS oncogene 1 receptor (ALK/ROS1) inhibitor ceritinib in combination with gemcitabine-based chemotherapy in patients with advanced solid tumors. Secondary objectives were characterization of the safety profile, pharmacokinetics and preliminary efficacy of these combinations, and identification of potential biomarkers of efficacy. Ceritinib was combined with gemcitabine (Arm 1), gemcitabine/nab-paclitaxel (Arm 2) or gemcitabine/cisplatin (Arm 3). Drug concentrations in plasma were measured by tandem mass spectrometric detection (LC-MS/MS). We analyzed archival tumor tissue for ALK, ROS1, hepatocyte growth factor receptor (c-MET) and c-Jun N-terminal kinase (JNK) expression by immunohistochemistry. Arm 2 closed early secondary to toxicity. Twenty-one patients were evaluable for dose-limiting toxicity (DLT). There was one DLT in Arm 1 (grade 3 ALT increase) and three DLTs in Arm 3 (grade 3 acute renal failure, grade 3 thrombocytopenia, grade 3 dyspnea). The MTD of ceritinib was determined to be 600 mg (Arm 1) and 450 mg orally daily (Arm 3). Main toxicities were hematologic, constitutional and gastrointestinal as expected by the chemotherapy backbone. The apparent clearance for ceritinib decreased substantially after repeated dosing; cisplatin did not significantly affect the pharmacokinetics of ceritinib. The overall response rate was 20%; the median progression-free survival was 4.8 months. Three out of five response-evaluable cholangiocarcinoma patients had clinical benefit. Increased expression of c-MET was associated with a lack of clinical benefit. Ceritinib in combination with gemcitabine and gemcitabine/cisplatin has a manageable toxicity profile. Further development of this strategy in tumors with ALK or ROS1 fusions is warranted.
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    A protein panel in cerebrospinal fluid for diagnostic and predictive assessment of alzheimer’s disease
    (American Association for the Advancement of Science, 2023) Haque, Rafi; Watson, Caroline M.; Liu, Jiaqi; Carter, E. Kathleen; Duong, Duc M.; Lah, James J.; Wingo, Aliza P.; Roberts, Blaine R.; Johnson, Erik C. B.; Saykin, Andrew J.; Shaw, Leslie M.; Seyfried, Nicholas T.; Wingo, Thomas S.; Levey, Allan I.; Radiology and Imaging Sciences, School of Medicine
    Alzheimer's disease (AD) is a neurodegenerative disease with heterogenous pathophysiological changes that develop years before the onset of clinical symptoms. These preclinical changes have generated considerable interest in identifying markers for the pathophysiological mechanisms linked to AD and AD-related disorders (ADRD). On the basis of our prior work integrating cerebrospinal fluid (CSF) and brain proteome networks, we developed a reliable and high-throughput mass spectrometry-selected reaction monitoring assay that targets 48 key proteins altered in CSF. To test the diagnostic utility of these proteins and compare them with existing AD biomarkers, CSF collected at baseline visits was assayed from 706 participants recruited from the Alzheimer's Disease Neuroimaging Initiative. We found that the targeted CSF panel of 48 proteins (CSF 48 panel) performed at least as well as existing AD CSF biomarkers (Aβ42, tTau, and pTau181) for predicting clinical diagnosis, FDG PET, hippocampal volume, and measures of cognitive and dementia severity. In addition, for each of those outcomes, the CSF 48 panel plus the existing AD CSF biomarkers significantly improved diagnostic performance. Furthermore, the CSF 48 panel plus existing AD CSF biomarkers significantly improved predictions for changes in FDG PET, hippocampal volume, and measures of cognitive decline and dementia severity compared with either measure alone. A potential reason for these improvements is that the CSF 48 panel reflects a range of altered biology observed in AD/ADRD. In conclusion, we show that the CSF 48 panel complements existing AD CSF biomarkers to improve diagnosis and predict future cognitive decline and dementia severity.
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    A proteomic meta-analysis refinement of plasma extracellular vesicles
    (Springer Nature, 2023-11-28) Vallejo, Milene C.; Sarkar, Soumyadeep; Elliott, Emily C.; Henry, Hayden R.; Powell, Samantha M.; Diaz Ludovico, Ivo; You, Youngki; Huang, Fei; Payne, Samuel H.; Ramanadham, Sasanka; Sims, Emily K.; Metz, Thomas O.; Mirmira, Raghavendra G.; Nakayasu, Ernesto S.; Pediatrics, School of Medicine
    Extracellular vesicles play major roles in cell-to-cell communication and are excellent biomarker candidates. However, studying plasma extracellular vesicles is challenging due to contaminants. Here, we performed a proteomics meta-analysis of public data to refine the plasma EV composition by separating EV proteins and contaminants into different clusters. We obtained two clusters with a total of 1717 proteins that were depleted of known contaminants and enriched in EV markers with independently validated 71% true-positive. These clusters had 133 clusters of differentiation (CD) antigens and were enriched with proteins from cell-to-cell communication and signaling. We compared our data with the proteins deposited in PeptideAtlas, making our refined EV protein list a resource for mechanistic and biomarker studies. As a use case example for this resource, we validated the type 1 diabetes biomarker proplatelet basic protein in EVs and showed that it regulates apoptosis of β cells and macrophages, two key players in the disease development. Our approach provides a refinement of the EV composition and a resource for the scientific community.
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    A set of circulating microRNAs belonging to the 14q32 chromosome locus identifies two subgroups of individuals with recent-onset type 1 diabetes
    (Elsevier, 2024) Sebastiani, Guido; Grieco, Giuseppina Emanuela; Bruttini, Marco; Auddino, Stefano; Mori, Alessia; Toniolli, Mattia; Fignani, Daniela; Licata, Giada; Aiello, Elena; Nigi, Laura; Formichi, Caterina; Fernandez-Tajes, Juan; Pugliese, Alberto; Evans-Molina, Carmella; Overbergh, Lut; Tree, Timothy; Peakman, Mark; Mathieu, Chantal; Dotta, Francesco; INNODIA investigators; Pediatrics, School of Medicine
    Circulating microRNAs (miRNAs) are linked to the onset and progression of type 1 diabetes mellitus (T1DM), thus representing potential disease biomarkers. In this study, we employed a multiplatform sequencing approach to analyze circulating miRNAs in an extended cohort of prospectively evaluated recent-onset T1DM individuals from the INNODIA consortium. Our findings reveal that a set of miRNAs located within T1DM susceptibility chromosomal locus 14q32 distinguishes two subgroups of individuals. To validate our results, we conducted additional analyses on a second cohort of T1DM individuals, confirming the identification of these subgroups, which we have named cluster A and cluster B. Remarkably, cluster B T1DM individuals, who exhibit increased expression of a set of 14q32 miRNAs, show better glycemic control and display a different blood immunomics profile. Our findings suggest that this set of circulating miRNAs can identify two different T1DM subgroups with distinct blood immunomics at baseline and clinical outcomes during follow-up.