Digital Commons Network^™

Biophysical Simulation Enables Segmentation And Nervous System Atlas Mapping For Image First Spatial Omics, Lina Mohammed Ali, Aldrin Kay Yuen Yim, Emanuel Gerbi, Thien Nguyen, Nicholas Tu, Faith Ikede, Remi Sampaleanu, Diana Grigore, Jason Waligorski, Colin Kremitzki, Liya Yuan, Wendy Dong, Robi Mitra, Jeffrey Milbrandt, William Buchser

2020-Current year OA Pubs

Spatial omics (SO) produces high-definition mapping of subcellular molecules within tissue samples. Mapping transcripts to anatomical regions requires segmentation, but this remains challenging in tissue cross-sections with tubular structures like axons in peripheral nerve or spinal cord. Neural networks could address misidentification but are hindered by the need for extensive human annotations. We present SiDoLa-NS (Simulate, Don't Label-Nervous System), an image-driven (top-down) approach to SO analysis in the nervous system. We utilize biophysical properties of tissue architectures to design synthetic images of tissue samples, eliminating reliance on manual annotation and enabling scalable training data generation. With synthetic samples, we trained …

Cardiometabolic And Molecular Adaptations To 6-Month Intermittent Fasting In Middle-Aged Men And Women With Overweight: Secondary Outcomes Of A Randomized Controlled Trial, Ruteja A Barve, Nicola Veronese, Beatrice Bertozzi, Valeria Tosti, Maria Lastra Cagigas, Francesco Spelta, Edda Cava, Laura Piccio, Dayna S Early, Richard D Head, Luigi Fontana

2020-Current year OA Pubs

Intermittent fasting (IF) has gained attention as a potential intervention for cardiometabolic health, though its long-term effects remain unclear. In this randomized clinical trial, we assessed the impact of 6 months of IF on body composition, cardiovascular risk factors, and related molecular pathways in middle-aged (30-65 years) men and women with overweight (BMI 24.8-35 kg/m²). In this trial, 41 participants were randomized to either an intermittent fasting (IF) intervention or to maintain their habitual diet. The primary outcome (circulating CRP concentration) was previously reported; here, we present exploratory analyses focusing on metabolomic and transcriptomic responses. IF led to an 8% …

Stakeholder Criteria For Trust In Artificial Intelligence-Based Computer Perception Tools In Health Care: Qualitative Interview Study, Ansh Rai, Meghan E Hurley, John Herrington, Eric A Storch, Casey J Zampella, Julia Parrish-Morris, Anika Sonig, Gabriel Lázaro-Muñoz, Kristin Kostick-Quenet

Faculty, Staff and Students Publications

Background: Computer perception (CP) technologies hold significant promise for advancing precision mental health care systems, given their ability to leverage algorithmic analysis of continuous, passive sensing data from wearables and smartphones (eg, behavioral activity, geolocation, vocal features, and ambient environmental data) to infer clinically meaningful behavioral and physiological states. However, successful implementation critically depends on cultivating well-founded stakeholder trust.

Objective: This study aims to investigate, across adolescents, caregivers, clinicians, and developers, the contingencies under which CP technologies are deemed trustworthy in health care.

Methods: We conducted 80 semistructured interviews with a purposive sample of adolescents (n=20) diagnosed with autism, Tourette …

Conservation Of Cis-Regulatory Codes Over Half A Billion Years Of Evolution, Yohey Ogawa, Yu Liu, Connie A Myers, Ala Morshedian, Gordon L Fain, Alapakkam P Sampath, Joseph C Corbo

2020-Current year OA Pubs

Identifying homologous cell types across species is essential for understanding cell type evolution. The retina is ideal for comparative analysis because its six major cell classes have persisted since the origin of vertebrates more than half a billion years ago. Here, we show that the retina's conserved cellular architecture is mirrored by deep conservation of the cis-regulatory codes that govern gene expression. Through single-cell chromatin accessibility analysis of lamprey, fish, bird, and mammalian retinas, we demonstrate cross-species conservation of cis-regulatory codes in all retinal cell classes despite extensive turnover of cis-regulatory regions. Conservation manifests as clustering of high-affinity transcription factor …

Early Genetic Evolution Of Driver Mutations In Uveal Melanoma, James J Dollar, Kisha D Piggott, Et Al.

2020-Current year OA Pubs

Uveal melanoma (UM) is an aggressive eye cancer that frequently results in metastatic death despite successful primary tumor treatment. Subclinical micrometastasis is thought to occur early, when tumors are small and difficult to distinguish from benign nevi. However, the early genetic evolution of UM is poorly understood, and biomarkers for malignant transformation are lacking. Here, we perform integrated genetic profiling of 1140 primary UMs, including 131 small tumors. A clinically available 15-gene expression profile (15-GEP) prospectively validated by our group is more accurate than driver mutations for predicting patient survival. Small tumors are significantly more likely to be in earlier …

A Qualitative Exploration Of Patient And Clinician Needs And Preferences For A Physical Activity Intervention During Breast Cancer Chemotherapy, D Carolina Andrade, Loni Parrish, Courtney Harriss, Lindsay L Peterson, Ryan P Duncan, Jingqin Luo, Maura M Kepper, Christine Marx, Mary C Politi, Elizabeth A Salerno

2020-Current year OA Pubs

BACKGROUND: Early intervention with physical activity (PA) during active cancer treatment is critical for improved health outcomes, but often difficult to deliver. We assessed patients' and clinicians' needs and preferences for a PA intervention during chemotherapy via semi-structured interviews.

METHODS: We conducted virtual semi-structured interviews from May 2022 to May 2023 with patients with stage I-III breast cancer and oncology clinicians recruited from a Midwestern comprehensive cancer center and community settings. We identified themes using deductive and inductive thematic analysis informed by the Consolidated Framework for Implementation Research.

RESULTS: Patients (n = 16) were mostly White, non-Hispanic (93.8%) females (100%) …

Concurrent Tb And Hiv Therapies Control Tb Reactivation During Co-Infection But Not Chronic Immune Activation, Riti Sharan, Yi Zou, Bindu Singh, Vinay Shivanna, Edward J Dick, Shannan Hall-Ursone, Xi Luo, Guanlin Guo, Shabaana A Khader, Xavier Alvarez, Jyothi Rengarajan, Zhao Lai, Smriti Mehra, Hulin Wu, Deepak Kaushal

Faculty, Staff and Student Publications

Most HIV-negative individuals exposed to Mycobacterium tuberculosis (Mtb) control infection as latent TB infection (LTBI), but HIV co-infection greatly increases progression to tuberculosis (TB), the leading cause of death in people living with HIV (PLHIV). Although combination antiretroviral therapy (cART) reduces LTBI reactivation, immune control of Mtb is not fully restored, as shown by persistent TB incidence in PLHIV on cART. In macaques, skewed pulmonary effector memory CD4⁺ T-cell (TEM) responses and new TB lesions persist despite cART. We hypothesize that concurrent anti-TB therapy with cART would improve bacterial control and immune restoration compared to cART alone. Using …

Evolutionarily Convergent Mechanism Of Formin Regulation Coordinates Actin Polymerization In Apicomplexan Parasites, Pengge Qian, Yong Fu, Jianwei Zeng, Michael J Naldrett, Rui Zhang, L David Sibley

2020-Current year OA Pubs

Apicomplexan parasites rely on actin-based motility for host cell invasion and for their dissemination. Although previous studies implicate formin 1 (FRM1) in governing this process in

Genetic Modifiers And Ascertainment Drive Variable Expressivity Of Complex Disorders, Matthew Jensen, Corrine Smolen, Anastasia Tyryshkina, Lucilla Pizzo, Jiawan Sun, Serena Noss, Deepro Banerjee, Matthew Oetjens, Hermela Shimelis, Cora M Taylor, Vijay Kumar Pounraja, Hyebin Song, Laura Rohan, Emily Huber, Laila El Khattabi, Ingrid Van De Laar, Rafik Tadros, Connie R Bezzina, Marjon Van Slegtenhorst, Janneke Kammeraad, Paolo Prontera, Jean-Hubert Caberg, Harry Fraser, Siddharth Banka, Anke Van Dijck, Charles Schwartz, Els Voorhoeve, Patrick Callier, Anne-Laure Mosca-Boidron, Nathalie Marle, Mathilde Lefebvre, Kate Pope, Penny Snell, Amber Boys, Paul J Lockhart, Myla Ashfaq, Elizabeth Mccready, Margaret Nowacyzk, Lucia Castiglia, Ornella Galesi, Emanuela Avola, Teresa Mattina, Marco Fichera, Maria Grazia Bruccheri, Giuseppa Maria Luana Mandarà, Francesca Mari, Flavia Privitera, Ilaria Longo, Aurora Curró, Alessandra Renieri, Boris Keren, Perrine Charles, Silvestre Cuinat, Mathilde Nizon, Olivier Pichon, Claire Bénéteau, Radka Stoeva, Dominique Martin-Coignard, Sophia Blesson, Cedric Le Caignec, Sandra Mercier, Marie Vincent, Christa L Martin, Katrin Mannik, Alexandre Reymond, Laurence Faivre, Erik Sistermans, R Frank Kooy, David J Amor, Corrado Romano, Joris Andrieux, Santhosh Girirajan

Faculty, Staff and Student Publications

Variable expressivity of disease-associated variants implies a role for secondary variants that modify clinical features. We assessed the effects of modifier variants on the clinical outcomes of 2,455 individuals with primary variants. Among 124 families with the 16p12.1 deletion, distinct rare and common variant classes conferred risks for specific developmental features, including short tandem repeats for neurological defects. Network analysis suggested distinct mechanisms involving 16p12.1 genes and secondary variants specific to each proband. Within disease and population cohorts of 976 individuals with the 16p12.1 deletion, we found opposing effects of secondary variants on clinical features across ascertainments. Additional analysis of …

Structural Basis Of Panx1 Permeation And Positive Modulation By Mefloquine, Yangyang Li, Zheng Ruan, Junuk Lee, Ian Orozco, Edward Zhou, Juan Du, Wei Lü

Department of Biochemistry and Molecular Biology Faculty Papers

Purinergic signaling relies on ATP release through exocytosis and large-pore channels. Large-pore channels permeate both small anions like chloride and large signaling molecules like ATP, but how this broad cargo selectivity is structurally controlled remains elusive. Here we investigate PANX1, a prototypical large-pore channel, and uncover structural plasticity at the extracellular entrance formed by seven tryptophan (W74) residues. The W74 sidechains are flexible, sampling conformations that range from a constricted state permissive only to chloride to a dilated state compatible with ATP. These states are coupled to variable cation-π interactions between W74 and arginine 75 (R75), suggesting a mechanism for …

A Nationwide Registry Study Of Surgical And Patient-Reported Outcomes Following Anterior Cervical Discectomy And Fusion: Part 2 - Cage With Versus Without Local Bone Graft, Daniel De Wilde, Victor Gabriel El-Hajj, Patrick Vigren, Victor E. Staartjes, Elias Atallah, Erik Edström, Adrian Elmi-Terander

Department of Neurosurgery Faculty Papers

BACKGROUND: Local bone grafts are commonly used as filling material in cages during anterior cervical discectomy and fusion (ACDF). Alternatively, cages without filling materials can be used. The literature comparing these approaches is limited, and their respective effects on patient-reported outcomes (PROM) have been scarcely studied. This study was conducted to compare surgical outcomes and PROMs between local bone graft-packed cages and empty cages in ACDF surgery.

METHODS: This observational study utilized data from the Swedish nationwide registry, Swespine. All adults who underwent ACDF between 2006 and 2020 were considered for inclusion. Exclusion criteria included missing baseline or outcome data. …

Effect Of Same-Day Hiv Treatment Initiation (Sdi) On 1-Year Outcomes In Low-And Middle -Income Countries: Systematic Review And Meta-Analysis Of Randomised Trials, Nikita Sass, Hanna Havrylenko, Felix Gerber, Alain Amstutz, Sydney Rosen, Alana Brennan, Mhairi Maskew, Serena Koenig, Nancy Dorvil, Elvin H Geng, Tracy Glass, Nathan P Ford, Niklaus Daniel Labhardt, Stefan Schandelmaier

2020-Current year OA Pubs

INTRODUCTION: Same-day initiation (SDI) of antiretroviral therapy is recommended for people presenting with HIV who have no contraindications. We reviewed the evidence on SDI interventions in low- and middle-income countries (LMICs).

METHODS: We conducted a systematic review and meta-analysis of randomised controlled trials of SDI in adults diagnosed with HIV in LMICs. We searched MEDLINE, Embase and the Cochrane Library up to December 2024. Primary outcomes were viral suppression and retention in care 6-12 months after enrolment. Based on a qualitative assessment of the complex trial interventions, we considered two subgroups: (1) interventions newly introducing SDI and (2) interventions improving …

Longitudinal Quality Improvement Project To Increase Colorectal Cancer Screening For An Underserved Population In A Resident Physician-Led Primary Care Clinic., Vivek Vardhan Jasti, Sarah N Grebennikov, Mariah Barlow, David Y Lo, Shail M Govani, Miram Chan, Aimee E Willett, Christopher Barlow

Medical Education Articles

BACKGROUND: The overall rates of colorectal cancer (CRC) in the US population have been declining steadily over the past 30 years, in large part due to timely cancer screenings. Despite the emergence of new screening modalities, a large portion of the population has not completed CRC screening in accordance with guidelines. Adequate and timely screening can prevent or detect CRC in earlier stages. Various factors have been identified that influence screening completion. Lower screening rates have been associated with the underserved population, especially in the immigrant community and patients with inadequate access to healthcare. In the USA, primary care clinics …

Camidanlumab Tesirine For Relapsed Or Refractory Classic Hodgkin Lymphoma: A Phase 2 Study, Alex F Herrera, Nancy L Bartlett, Et Al.

2020-Current year OA Pubs

Outcomes in classic Hodgkin lymphoma (cHL) have steadily improved; however, additional therapies are needed for patients who relapse or do not respond to novel agents. Here, we report the efficacy and safety of camidanlumab tesirine (Cami), an anti-CD25 antibody-drug conjugate, in patients with relapsed/refractory cHL after brentuximab vedotin/programmed cell death protein 1 inhibitor therapies from the phase 2 ADCT-301-201 study. Eligible patients were adults with cHL who had received ≥3 previous lines of systemic therapy (or ≥2 if ineligible for hematopoietic stem cell transplant). Patients received 45 μg/kg Cami (IV, once every 3 weeks) in cycles 1 to 2, followed …

Glycoside Hydrolase-Mediated Glucomannan Catabolism In Segatella Copri, A Target Of Microbiota-Directed Foods For Malnourished Children, Cyrus Zhou, Matthew C Hibberd, Evan M Lee, Suzanne Henrissat, Marie A Crane, Jiye Cheng, Michael J Barratt, Jeffrey I Gordon, Et Al.

2020-Current year OA Pubs

Evidence is emerging that perturbed postnatal gut microbiota development is causally related to childhood undernutrition. Clinical trials in undernourished Bangladeshi children found that a polysaccharide-rich, microbiota-directed complementary food (MDCF-2) designed to repair this perturbation produced superior ponderal and linear growth compared to a standard ready-to-use supplementary food. Subsequent analyses disclosed several candidate bioactive polysaccharides in the MDCF and their bacterial targets, notably strains of

Association Of Pet4 Response With Outcomes Of Bv-Chp Vs Chop In The Echelon-2 Trial In Cd30+ Peripheral T-Cell Lymphoma, Swaminathan Iyer, Neha Mehta-Shah, Nancy L Bartlett, Et Al.

2020-Current year OA Pubs

In the phase 3 ECHELON-2 trial, brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (BV-CHP) significantly improved progression-free survival (PFS) and overall survival (OS) compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in patients with CD30+ peripheral T-cell lymphoma, benefits that were maintained at 5 years. Interim positron emission tomography (PET) scan can be used to assess prognosis and risk-stratify patients. The prognostic value of interim PET was assessed in this post hoc exploratory analysis from ECHELON-2, evaluating interim 18F-fluorodeoxyglucose PET scans after cycle 4 (PET4) and end-of-treatment-based response, and correlated with PFS per investigator and OS. PET4 response was determined by …

Deep Profiling Of Human T Cells Defines Compartmentalized Clones And Phenotypic Trajectories Across Blood And Tonsils, Suhas Sureshchandra, Elizabeth Levendosky, Allyssa Daugherty, Samuel J H Murphy, Chandrani Thakur, Naresha Saligrama, Et Al.

2020-Current year OA Pubs

98% of T cells reside in tissues, yet nearly all human T cell analyses are performed on peripheral blood. We performed single-cell sequencing of 5.7 million T cells from autologous blood and tonsils of ten donors. We identified distinct patterns of clonal expansion associated with tonsil-restricted phenotypes. Clonal sharing between blood and tonsils was lower than previous estimates and increased with age. Identical T cell receptor (TCR) sequences exhibited limited concordance in their phenotypes across compartments. Furthermore, location dictated the frequencies, clonal dominance, and phenotypes of antigen-specific T cells. Using immune organoids, we showed that antigen exposure drives functionally distinct …

Consensus-Based Expert Recommendations For Diagnosis And Clinical Management Of Vanishing White Matter., Romy J. Van Voorst, Daphne H. Schoenmakers, Joshua L. Bonkowsky, Adeline Vanderver, Ingeborg Krägeloh-Mann, Geneviève Bernard, Enrico Bertini, Ali Fatemi, Paulo V. Sgobbi, Nicole I. Wolf, Samuel Groeschel, Davide Tonduti, Caroline Sevin, Jennifer L. Orthmann-Murphy, Ludger Schöls, Ettore Salsano, Bernard Brais, Nicole Jaffe, Kasper W. Ter Horst, Sabine E. Hannema, Katherine G. Hayes, Jochen Meyburg, Marc Van Heerde, Anne Marie Sbrocchi, Rosalina Van Spaendonk, Isabelle Thiffault, Geesje H. Hofsteenge, Carolina Sudmeier-Broek, Corrie Timmer, Donna Skwirut, Allyson Buck, Bret Hollberg, Ron Chapleau, Hanka Dekker, Susan G. Campbell, Truus E M Abbink, Prisca S. Leferink, Marjo S. Van Der Knaap

Manuscripts, Articles, Book Chapters and Other Papers

Vanishing white matter (VWM) is a rare disorder, characterized by degeneration of CNS white matter, clinically often exacerbated by stressors such as fever and minor head trauma. VWM is caused by biallelic pathogenic variants in the EIF2B1-5 genes, causing reduced activity of eukaryotic initiation of translation factor 2B, resulting in dysregulation of the integrated stress response (ISR). New scientific insights and increased clinical trials in experimental therapies highlight the need for clinical guidelines to improve and standardize care for patients with VWM worldwide. Standardized care is important for therapy development, as it lessens clinical variability of trial participants at study …

Myocardial Lipin1 Protects The Heart Against Ischemic Injury By Preserving Lipid Homeostasis, Jiaxi Guo, Brian N. Finck, Et Al.

2020-Current year OA Pubs

Impaired cardiac lipid metabolism has been reported to cause heart failure. Lipin1, a multifunctional protein, is a phosphatidate phosphatase that generates diacylglycerol from phosphatidic acid and a transcriptional cofactor that regulates lipid metabolism-related gene expression. Here, we investigated the roles of lipin1 in cardiac remodeling after myocardial infarction (MI). The expression levels of lipin1 significantly decreased in cardiomyocytes of the human failing heart and murine ischemic myocardium. Cardiomyocyte-specific Lpin1 knockout (cKO) mice showed left ventricle enlargement and reduced fractional shortening after MI, compared with control mice. This was accompanied by elevated cardiac fibrosis, accumulation of reactive oxygen species, and increased …

Artem-Is For Erp: Agreed Reporting Template For Eeg Methodology-International Standard For Event-Related Potential Experiments, Giorgio Ganis

School of Psychology

The choices we make during the recording, preprocessing and analysis of event-related potentials (ERP) data can affect study outcomes. As such, it is critical that they are transparently reported to allow for reproducibility. Yet, systematic reviews of reporting practices in the field have shown that journal articles often do not meet this goal and that existing reporting guidelines have not resulted in a sufficient improvement in reporting transparency. An easier workflow for transparently documenting pipelines used in regular journal articles is needed. The ARTEM-IS (Agreed Reporting Template for EEG Methodology—International Standard) initiative is working towards addressing this issue by building …

Insm1 Governs A Neuronal Progenitor State That Drives Glioblastoma In A Human Stem Cell Model, Patrick A Desouza, Matthew Ishahak, Xuan Qu, Colin Mccornack, Devi Annamalai, Diane D Mao, Rajanikanth Vangipurapu, Yiwei Fu, Alexandre T Vessoni, Ryan T Cleary, Rowland H Han, Punn Augsornworawat, Timothy Woodiwiss, Darby Agovino, Braxton Sizemore, Jessica Kline, Maryam Borhani-Haghighi, Hao Chen, Sangami Pugazenthi, Hiroko Yano, Ting Wang, Luis F Z Batista, Jeffrey R Millman, Albert H Kim

2020-Current year OA Pubs

Glioblastoma is a lethal brain cancer marked by functional plasticity driven by tumor cell-intrinsic mutations and their interplay with developmental programs. To investigate how canonical glioblastoma mutations promote functional plasticity, we have developed an isogenic human neural stem cell (NSC) model of glioblastoma by sequential addition of TERT promoter, TP53, and PDGFRA point mutations. TP53 loss-of-function increases TERT expression during serial mutagenesis, but only triple mutant NSCs reliably form lethal brain tumors in vivo that recapitulate glioblastoma. Tumor cell evolution triggers stress-related metabolic changes and transitions toward a neuronal progenitor network driven by transcription factor INSM1. INSM1 is highly expressed …

Patient-Centered Televisit For Chronic Obstructive Pulmonary Disease Discharge Transitions: User-Centered Design Study, Joanna Abraham, Alicia Meng, Nicolas Caravelli, Leah Traeger, May Nguyen, Vineet Arora, Valerie G Press

2020-Current year OA Pubs

BACKGROUND: Chronic obstructive pulmonary disease (COPD) affects approximately 16 million Americans and often results in avoidable readmissions due, in part, to medication errors and lack of education. Telehealth interventions can support medication reconciliation and inhaler education following hospital discharge for patients with COPD.

OBJECTIVE: This study aimed to design and prototype TELE-TOC (Telehealth Education: Leveraging Electronic Transitions of Care), a post-discharge, in-home, televisit intervention, and to map its workflow to ensure integration into the routine discharge care transition process for patients with COPD.

METHODS: A user-centered design approach across 3 phases was followed to develop and prototype TELE-TOC. Participants included …

Synergistic Potential Of Sipuleucel-T In Enhancing Immunotherapy For Metastatic Castration-Resistant Prostate Cancer, Kavita Rawat, Varnika Punia, Parker Mathews, Sara Mccoy, Wilbur Song, Muhammad A Saeed, Russell K Pachynski

2020-Current year OA Pubs

Clinical trials of immunotherapy in metastatic castration-resistant prostate cancer (mCRPC) have largely been unsuccessful despite promising preclinical studies and proven efficacy in other solid tumors. These disappointing clinical outcomes have been attributed to an immunosuppressive tumor microenvironment, a relative lack of infiltrating immune effector cells, and tumor-related and host-related factors, which collectively render prostate cancer a relatively immunologically "cold" tumor. Sipuleucel-T (Provenge), an autologous cellular immunotherapy, induces an immune response targeted against prostatic acid phosphatase. It received approval from the US Food and Drug Administration in 2010, marking the first immunotherapy to show an overall survival benefit in patients with …

Inhibitory Control, Attentional Bias, And Palatable Food Consumption In Adolescents: A Laboratory Feasibility Randomized Controlled Trial., Carolina M. Bejarano, Adrian Ortega, Christopher C. Cushing

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Understanding relationships among inhibitory control, attentional bias to food cues, and food consumption in nonclinical adolescent samples can inform preventive efforts for disordered eating and associated health risks.

OBJECTIVE: This pilot study conducted preliminary testing of an inhibitory control training intervention on attentional bias toward food cues, hedonic appetite, and food consumption, as well as examined inhibitory control's relationship with hedonic appetite, food consumption, binge eating, and cognitive restraint.

METHODS: Participants (N=43; mean age 15.1, SD 1.7 years; 31/43, 72% female) were randomized to a food cue-specific go/no go inhibitory control training intervention or control group, took part in …

Laboratory Monitoring In Patients With Moderate To Severe Plaque Psoriasis, Jonathan M. Fenkel, John A. Osborne, April W. Armstrong, Bruce Strober, Linda Stein Gold, Michael Cameron, Mark Lebwohl

Department of Medicine Faculty Papers

OBJECTIVES: Plaque psoriasis is a common immune-mediated disease associated with various comorbidities, including cardiovascular disease, diabetes, psoriatic arthritis, liver disease, and mood disorders. Biologic and small-molecule therapies are efficacious and well tolerated in adults with moderate to severe plaque psoriasis. However, dermatologists may be uncertain about appropriate laboratory monitoring in patients treated with these therapies, especially those with comorbidities.

METHODS: This review summarizes prescribing information and provides expert recommendations based on real-world experience in the monitoring of concerning laboratory values in patients with psoriasis.

RESULTS: Individualized monitoring is essential for maximizing the benefits and minimizing the risks associated with biologic …

Discovery Of A Small Molecule Tlr3 Agonist Adjuvant, Branden Lee, Danica Dong, Etsuro Nanishi, John Mark Awad, Kimia Abedi, Yoshine Saito, Francesco Borriello, Soumik Barman, Byron Brook, Aisling Kelly, Manisha Menon, Constance Marques-Mourlet, Maansi Gupta, Ida Lister, Chiwoo Oh, Kevin Lyskawa, Morgan Goetz, Kristina Walker, Wing Ki Cheng, Spencer Brightman, Pankaj Sharma, Timothy O'Meara, Katherine Chew, Daniel Vieira, Kevin Ryff, Cali Sweitzer, Sanya Thomas, Simon Van Haren, Matthew Pettengill, Hyuk-Soo Seo, Sirano Dhe-Paganon, Wei Zhang, Ofer Levy, David Dowling

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Pattern-recognition receptor (PRR) agonists are valuable agents across multiple medical applications, from vaccinology to immune-oncology. However, well-defined and potent small molecule agonists for many PRRs still await discovery and development. Screening of chemical libraries of ~200,000 small molecules for maturation of human monocytic cells by quantifying NF-κB activation and cell adherence was completed. From this screen, we selected a thiazole benzamide derivative, PVP-057, for its robust immunomodulatory properties, low toxicity profile, and concentration-dependent activity. In vitro investigation of pathway and receptor activation reveals that PVP-057 is a Toll-like receptor 3 (TLR3) agonist. As a single-component adjuvant, administered intramuscularly or intradermally …

Can Cta-Based Machine Learning Identify Patients For Whom Successful Endovascular Stroke Therapy Is Insufficient?, Jerome A Jeevarajan, Yingjun Dong, Anjan Ballekere, Sergio Salazar Marioni, Arash Niktabe, Rania Abdelkhaleq, Sunil A Sheth, Luca Giancardo

Faculty, Staff and Student Publications

Background and purpose: Despite advances in endovascular stroke therapy (EST) devices and techniques, many patients are left with substantial disability, even if the final infarct volumes (FIVs) remain small. Here, we evaluate the performance of a machine learning (ML) approach by using pretreatment CTA to identify this cohort of patients that may benefit from additional interventions.

Materials and methods: We identified consecutive subjects with large vessel occlusion (LVO) acute ischemic stroke (AIS) who underwent EST with successful reperfusion in a multicenter prospective registry cohort. We included only subjects with FIV < 30 mL and recorded 90-day outcome (mRS). A deep learning model was pretrained and then fine-tuned to predict 90-day mRS 0-2 by using pretreatment CTA images (DeepsymNet-v3 model pretrained on radiology reports and fine-tuned on detection of unexpected clinical outcomes using brain CTA images [DSN-CTA] model). The primary outcome was the predictive performance of the DSN-CTA model compared with a logistic regression model with clinical variables, measured by the area under the receiver operating characteristic curve (AUROC).

Results: The DSN-CTA model was pretrained on 1542 subjects and …

Functional Classification Of Platelet Gene Variants Using Crispr Hdr In Cd34+ Cell-Derived Megakaryocytes, Yasuhiro Kosaka, Brandon Lopez, Nina Kishimoto, Shancy Jacob, Emilie Montenont, Rodrigo Huallanca, Graeson Coughenour, Jorge Di Paola, Justyne Ross, Kristy Lee, Matthew T Rondina, Paul F Bray, Jesse W Rowley

2020-Current year OA Pubs

The interpretation of genetic variants in inherited diseases, such as inherited platelet disorders (IPDs), remains a major clinical challenge, as most are classified as variants of uncertain significance (VUSs). A key barrier to functional evaluation is the lack of accessible, lineage-appropriate assays that reliably reflect native gene regulation and cell-specific biology. To address this gap, we developed CRIMSON HD (CRISPR-edited megakaryocytes [MKs] for surveying platelet variant functions through homology-directed repair [HDR]), a CRISPR-Cas9 HDR-based genome-editing platform applicable to CD34

Brain Metabolic-Functional (De)Coupling From Health To Glioma Dysfunction, G Vallini, G Baron, E Silvestri, T Volpi, A G Vlassenko, M S Goyal, A Chiuso, D Cecchin, M Corbetta, A Bertoldo

2020-Current year OA Pubs

The interplay between brain metabolism and function supports the brain's adaptive capacity in cognitively demanding processes. Prior work has linked glucose metabolism to resting-state fMRI activity, but often overlooks both hemodynamic confounders in the BOLD signal and the brain's dynamic nature. To address this, we employed a novel effective connectivity decomposition, separating symmetric partial covariance, capturing "true" statistical dependencies between regions, from antisymmetric differential covariance, reflecting directional brain flow. In 42 healthy subjects, we show that partial covariance corresponds to metabolic connectivity across regions, while node directionality relates to standardized uptake value ratio, a proxy for local glucose consumption. We …

Hsp90 Buffers Deleterious Genetic Variations In Brca1, Brant Gracia, Xing-Han Zhang, Patricia Montes, Tin Chanh Pham, Min Huang, Junjie Chen, Georgios Ioannis Karras

Faculty, Staff and Student Publications

Protein-folding chaperone heat shock protein 90 (HSP90) buffers genetic variation in diverse organisms, but the clinical significance of HSP90 buffering in human disease remains unclear. Here, we show that HSP90 buffers mutations in the BRCT domain of BRCA1. HSP90-buffered BRCA1 mutations result in protein variants that retain interactions with partner proteins and strongly rely on HSP90 for protein stability and function in cell survival. Moreover, HSP90-buffered BRCA1 variants confer poly (ADP-ribose) polymerase (PARP) inhibitor resistance in cancer cells. Low-level HSP90 inhibition overcomes this resistance, revealing a cryptic and mutant-specific HSP90-contingent synthetic lethality. Furthermore, by stabilizing metastable variants across the entirety …