Digital Commons Network^™

Feasibility And Usage Of A Virtual Assistant Device In Cognitively Impaired Homebound Older Adults, Matthew Nunez, Prisha Patel, Lindsey Ulin, Leslie Kian, Martin Cominsky, Jason Burnett, Jessica L Lee

Faculty, Staff and Student Publications

Social technology in older adults can improve self-rated health; however, there can also be difficulties using it. Our study aimed to evaluate the feasibility and acceptance of virtual assistant device (VAD) use in cognitively impaired homebound older adults. 52 newly referred Meals on Wheels clients aged 60 and older were recruited for a three-phase study: 6 weeks of meals alone (control), followed by 6 weeks of meals+Alexa Echo Show 8 (AES8) basic usage, and lastly 6 weeks of meals+AES8 advanced usage. Technology acceptance with the AES8 was significantly higher by the end of the study and participants anecdotally enjoyed playing …

Improving The Discussion Of Suicide Prevention: A Quality Improvement Project, Chelsea Reynolds, Alyssa Zeitouni, Kathryn Stephenson

Clinical Practice in Athletic Training

Suicide is currently the second leading cause of death among adolescents in the United States and the third leading cause of death in this age group worldwide.1,2 Suicide prevention is understandably a growing focus in pediatrics. Currently, at the Children’s Hospital Outpatient Clinic, that is staffed by pediatric resident physicians, suicidal ideation is screened for using a PHQ-9 screen. However, at the time this study was initiated and completed, the TEEN screen was utilized. After the screening is performed, regardless of type, it is up to the provider to address these findings in a safe and effective manner. The goal …

Alterations In Region-Specific Gray Matter Volume Underlying Callous Unemotional Traits In Adolescents, Johannah Bashford-Largo, Ru Zhang, R James R Blair, Karina S Blair, Jaimie Elowsky, Matthew Dobbertin, Ahria J Dominguez, Melissa Hatch, Tyler Patrick, Sahil Bajaj

Faculty, Staff and Student Publications

Background: Callous-unemotional (CU) traits during adolescence, for example, shallow affect or lack of remorse, have been shown to be a risk marker for antisocial behavior. Only a few studies have investigated structural brain alterations underlying CU traits, and findings are inconclusive. The study examines CU symptomatology and gray matter volume (GMV) associations.

Methods: Structural brain MRI data were collected from a sample of 578 adolescents (60% male) with a mean age of 14.85 years (SD = 2.30; range = 10-19 years). CU traits were indexed via the Inventory for Callous Unemotional Traits (ICU). Region-wise volumetric parameters were obtained following parcellation …

Tirzepatide For The Maintenance Of Body Weight Reduction: Rationale, Design, And Baseline Characteristics Of Surmount-Maintain, Deborah B Horn, Louis J Aronne, Sean Wharton, Harold E Bays, Elisa Gomez-Valderas, Avigdor D Arad, Palash Sharma, Julia P Dunn, Cagri Senyucel, Clare J Lee

Faculty, Staff and Student Publications

Objective: SURMOUNT-MAINTAIN aims to evaluate the efficacy and safety of reducing the tirzepatide dose and/or continuing the maximum tolerated dose (MTD) versus placebo in maintaining body weight (BW) reduction achieved with tirzepatide MTD.

Methods: This Phase 3b, multicenter, randomized, parallel-arm, double-blinded, placebo-controlled, 52-week clinical trial is in progress comparing treatment with once weekly tirzepatide (5 mg and/or MTD of 15 mg or 10 mg) versus placebo in achieving BW reduction maintenance from the initial 60-week open-label weight-loss period on tirzepatide MTD, in adults with obesity (BMI ≥ 30 kg/m2 or ≥ 27 kg/m2 with ≥ 1 obesity-related comorbidity, excluding type …

Tofacitinib Ameliorates Campylobacter-Induced Intestinal Pathology By Suppressing Ifnγ Producing Ilcs And T Cells, Anna A Korchagina, Sergey A Shein, Wayne T Muraoka, Justin Nguyen, Qiangxing Chen, Anna A Tumanova, Austin W Todd, Carlos E Rivera, Rita Tamayo, Paolo Casali, Ekaterina Koroleva, Alexei V Tumanov

Faculty, Staff and Student Publications

Patients with autoimmune diseases are more susceptible to foodborne infections, which can be exacerbated by immunosuppressive therapy. Tofacitinib, a JAK/STAT pathway inhibitor, was recently approved for the treatment of ulcerative colitis, yet its effects on the pathogenesis of intestinal infections remain unclear. Here, we examined the impact of oral tofacitinib treatment in a mouse model of Campylobacter jejuni (C. jejuni) infection. Our results show that early tofacitinib administration attenuates intestinal pathology without affecting bacterial colonization. Specifically, tofacitinib suppressed CXCL1, CXCL2, CCL2 chemokine expression by intestinal epithelial cells, limiting recruitment of monocytes and neutrophils to the gut. In addition, JAK/STAT inhibition …

Tracking Change: A Follow-Up On The Culturally Adapted ¡Iniciando! La Adultez Program, Antonio F Pagán, Katherine A Loveland, Ron Acierno

Faculty, Staff and Student Publications

Introduction: Research on interventions for Latino young adults with Autism Spectrum Disorder (ASD) and their families often faces challenges in long-term engagement. This study aimed to assess the feasibility and effectiveness of the culturally adapted ¡Iniciando! La Adultez program through a long-term follow-up.

Methods: A cohort of Latino young adults with ASD and their families who participated in the ¡Iniciando! La Adultez program were followed for six months post-intervention. Participants were assessed at three and six months to evaluate continued engagement and outcomes. Retention rates at each follow-up point were calculated.

Results: The study demonstrated high retention rates, with 48 …

Covid-19 Booster Vaccine Messaging In Emergency Departments: A Cluster Randomized Clinical Trial, Melanie F Molina, Stephanie A Eucker, Kristin L Rising, Efrat R Kean, Zubaid Rafique, Heba Mesbah, David V Glidden, Mireya I Arreguin, Christopher Alvarez, Robert M Rodriguez

Faculty, Staff and Students Publications

Importance: Patient uptake of updated COVID-19 vaccines is crucial for reducing severe outcomes, yet national uptake remains low.

Objective: To determine if tailored messaging or simple inquiry about vaccine acceptance increases 30-day uptake of updated COVID-19 vaccines among emergency department (ED) patients.

Design, setting, and participants: This 3-arm, cluster randomized clinical trial conducted from January 29 to June 18, 2024, enrolled adult ED patients who had not received a COVID-19 vaccine in the prior 6 months across 6 EDs in San Francisco, California; Philadelphia, Pennsylvania; Houston, Texas; and Durham, North Carolina.

Interventions: Intervention M involved tailored messaging about updated COVID-19 …

Traumatic Brain Injury In Pregnancy: A Single Level I Trauma Center Experience, Hector Fuentes Plata, Nisha K Dabhi, Shankar P Gopinath, Spyridoula Tsetsou

Faculty, Staff and Students Publications

Traumatic brain injury (TBI) is less common in pregnancy than in the general population; however, it poses significant challenges in diagnosis and management. These include the potential teratogenicity of medications, radiation exposure from imaging modalities, physiological changes associated with pregnancy, and obstetric complications that may arise. Although there are general guidelines for trauma in the obstetric patient, they are not specific to TBI, and most recommendations are based on low-level evidence or institutional experiences.

We conducted a retrospective review of the hospital trauma registry over a 10-year period. We included all the patients admitted to our neurosurgical intensive care unit …

Carbonic Anhydrase Inhibition Sensitizes Group 3 Medulloblastoma To Radiotherapy, Cory M Richman, Alexandra Rasnitsyn, Borja L Holgado, Maria Vladoiu, Namal Abeysundara, Sandra Majo, Sara Chabi, Lucie J Taunay, Hiromichi Suzuki, Ichiyo Shibahara, Joonas Haapasalo, Jonelle G Pallotta, Tajana Douglas, Kaitlin Kharas, Kyle Juraschka, Oliver Ocsenas, Sachin A Kumar, Kristiina Nordfors, Ana Guerreiro Stücklin, Raul A Suarez, Jiao Zhang, Xiaochong Wu, Craig Daniels, Livia Garzia, Jüri Reimand, Olivier Saulnier, Thomas E Merchant, Celio Pouponnot, David R Raleigh, Michael D Taylor, Pasqualino De Antonellis

Faculty, Staff and Students Publications

Group 3 (G3) medulloblastoma constitutes the most aggressive molecular subgroup, and nearly all patients present with metastases upon recurrence. Treatment for newly diagnosed medulloblastoma relies on a combination of maximal safe surgical resection, followed by chemotherapy and ionizing radiation, and no therapies have been shown to confer a survival benefit at the time of recurrence. Given the limited therapeutic options available for patients with medulloblastoma, especially at recurrence, and the incomplete understanding of the molecular mechanisms underlying resistance to treatment, we sought to uncover actionable targets and biomarkers that could help refine patient selection and treatment of newly diagnosed medulloblastoma …

Alternative Polyadenylation Contributes To Fibroblast Senescence In Pulmonary Fibrosis, Jingjing Huang, Maria Jose Gacha-Garay, Yu Wang, Scott D Collum, Rene A Girard, Hydia Puente, Seung-Hee Yoo, Rahat Hussain, Jayeshkumar Patel, Manish Patel, Eric J Wagner, Hari Krishnayalamanchili, Harry Karmouty-Quintana, Zheng Chen, Tingting Mills

Faculty, Staff and Students Publications

Idiopathic pulmonary fibrosis (IPF) is a prevalent and deadly age-related disease characterized by chronic, progressive, and irreversible fibrosis. A key effector cell population in the fibroproliferative response is the fibroblasts. Fibroblast cell senescence gradually worsens during aging, and the acquisition of a senescence-associated secretory phenotype (SASP) turns senescent fibroblasts into pro-inflammatory cells. However, the mechanism promoting senescence in IPF, especially at the post-transcriptional level, is poorly understood. We recently discovered that Nudix Hydrolase 21 (NUDT21, also named CFIm25), an RNA-binding protein, plays a critical role in regulating the expression of SASP factors through alternative polyadenylation (APA). APA allows adding poly(A) …

Complexity And Health Care Utilization In Infant Eskd, Ashna R Pudupakkam, Michael C Braun, Catherine Joseph, Poyyapakkam R Srivaths, Sarah J Swartz, Shweta S Shah

Faculty, Staff and Students Publications

Key Points:

1. Infant ESKD is associated with significant health care utilization including hospitalizations, subspecialty care, and financial expenditures.

2. Further investigation of health care utilization in infant ESKD can help guide the appropriate allocation of resources to support care delivery.

Background: Dialysis in neonates with ESKD is often associated with multiple comorbidities and the need for more intensified dialysis regimens. With recent advances in prenatal interventions and infant-specific KRT, survival of neonates with ESKD has improved over the past decade. Little is known, however, about the impact on the health care system of improved survival in this population. Our primary aim …

Endoglin-Directed Car T Cells Comprehensively Target Tumors In Advanced Sarcomas, Harrison R Berger, Malina Maharana, Jeneffer Mirabal, Lyazat Kurenbekova, Alberto Delaidelli, Atreyi Dasgupta, Ahmed Z Gad, Mohamed F Sheha, Sybrina S Kerr, Ada I Ozcan, Jessica S Morris, Angela M Major, M John Hicks, Mary K Mckenna, Ben K Seon, Matthew L Baker, Poul H Sorensen, Meenakshi Hegde, Jason T Yustein, Nabil Ahmed, Sujith K Joseph

Faculty, Staff and Students Publications

There are limited therapeutic options for patients with advanced sarcomas, which leads to dismal outcomes for children and adults. Although chimeric antigen receptor (CAR) T cells hold promise for treating advanced sarcomas, this approach is constrained by a paucity of effective targets. Our previous clinical study identified endoglin (ENG/CD105), a TGFβ coreceptor, as a target of the endogenous immune response in a patient with sarcoma who exhibited an exceptional response to HER2-targeted CAR T-cell therapy. ENG is expressed on various sarcomas, cancer-associated fibroblasts, and neoangiogenic vessels and therefore offers comprehensive tumor targeting. Furthermore, ENG knockout in sarcoma cells reduces their …

Transdiagnostic Correlates Of Family Accommodation In Anxious Youth, Whitney S Shepherd, Erika S Trent, Orri Smarason, Hannah N Sansone, Daphne M Ayton, Amanda Palo, Abigail E Candelari, Wayne K Goodman, Andrew G Guzick, Eric A Storch

Faculty, Staff and Students Publications

Anxiety disorders are common in children and cause significant impairment. Family accommodation, which refers to behavioral changes that family members make to temporarily alleviate a child’s anxiety, has been linked to child anxiety symptom severity. Although emotional vulnerabilities for anxiety such as emotion dysregulation, anxiety sensitivity, and distress intolerance have been associated with family accommodation, research concerning the relationship between these constructs among anxious youth is limited. We hypothesized that these variables would be uniquely and positively associated with family accommodation and would moderate the relationship between anxiety symptom severity and family accommodation. Treatment-seeking child–parent dyads (N = 90; …

Protein Kinase Rock1 Activates Mitochondrial Fission Linking To Oxidative Stress And Muscle Atrophy, Meijun Si, Jihong Chen, Rizhen Yu, Hongchun Lin, Feng Li, Sungyun Jung, Sandhya S Thomas, Farhard R Danesh, Yanlin Wang, Hui Peng, Zhaoyong Hu

Faculty, Staff and Students Publications

Introduction: Chronic kidney disease (CKD) is associated with protein-energy wasting, characterized by a reduction in muscle mass and strength. Although mitochondrial dysfunction and oxidative stress are implicated in the pathogenesis of muscle wasting, underlying mechanisms remain unclear.

Methods: Here, we used transcriptomic analysis, metabolomics analyses, and mouse gene manipulation to investigate the effects of mitochondrial plasticity and oxidative stress on muscle wasting the subtotal nephrectomy mouse models of CKD. The mice with CKD were age- and sex-matched to sham-operated controls.

Results: Through these approaches, Rho-associated kinase ROCK1 emerged as a key molecule responsible for the observed mitochondrial fission and oxidative …

Is Bedtime Use Of Kratom (Mitragyna Speciosa) A Sleep Aid Or Disruptor? Examining Its Daily Effects And Individual Differences, Chung Jung Mun, Patricia Timmons, Leigh V Panlilio, Christopher D Verrico, Ynhi T Thomas, C Austin Zamarripa, David H Epstein, Kirsten E Smith

Faculty, Staff and Students Publications

Kratom (Mitragyna speciosa) is a psychoactive botanical native to Southeast Asia increasingly used in the U.S. for various self-reported benefits, including sleep improvement. However, empirical evidence concerning kratom’s effects on sleep is limited. Here, we examined the association between bedtime kratom use and self-reported sleep outcomes in naturalistic settings across consecutive days, while also exploring sex and chronic pain status as potential moderators. A secondary analysis was conducted using the data from a 15-day ecological momentary assessment (EMA) study of 357 U.S. adults who reported regularly using kratom. Participants made daily reports of their bedtime kratom use and …

Inhibition Of Ros1 Activity With Lorlatinib Reversibly Suppresses Fertility In Male Mice, Yuki Oyama, Kentaro Shimada, Haruhiko Miyata, Rie Iida-Norita, Chihiro Emori, Maki Kamoshita, Seiya Oura, Ryohei Katayama, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

Background: Inhibition of sperm maturation in the epididymis is a promising post-testicular strategy for short-acting male contraceptives. It has been shown that ROS1, a receptor tyrosine kinase expressed in the epididymis, is essential for epididymal differentiation, sperm maturation, and male fertility in mice. However, it is unknown if inhibition of ROS1 suppresses male fertility reversibly.

Objectives: Our study aimed to investigate the effects of ROS1 inhibitor administration in male mice on sperm function and fertility.

Materials and methods: We used lorlatinib, an anti-cancer drug that inhibits ROS1. We treated 10-week-old sexually mature male mice with lorlatinib for 3 weeks and …

Germline Cancer Predisposition Results From The National Cancer Institute-Children's Oncology Group Pediatric Match Trial, Sarah Scollon, Sharon E Plon, Steven Joffe, Jaclyn A Biegel, Shashikant Kulkarni, George Miles, David R Patton, Brent Coffey, Cynthia L Winter, Gregory J Tsongalis, Mark J Routbort, Nilsa C Ramirez, Lauren Saguilig, Jin Piao, Todd A Alonzo, Stacey L Berg, Elizabeth Fox, Brenda Weigel, Douglas S Hawkins, Jeffrey S Abrams, Margaret Mooney, Naoko Takebe, James V Tricoli, Katherine A Janeway, Nita L Seibel, D Williams Parsons

Faculty, Staff and Students Publications

Purpose: Precision oncology trials have generally focused on tumor testing to identify actionable alterations. The National Cancer Institute-Children's Oncology Group Pediatric MATCH trial incorporated return of germline results to assess feasibility of reporting in a cooperative group setting and characterize germline cancer predisposition in patients with refractory cancers.

Patients and methods: Tumor and blood DNA from patients 1-21 years of age with treatment-refractory solid tumors, non-Hodgkin lymphomas, or histiocytic disorders underwent cancer gene panel sequencing. Clinical germline reports returned to 151 study sites included pathogenic/likely pathogenic (P/LP) germline variants found in 38 cancer predisposition genes (CPGs). European Society of Medical …

Nrf2 Hyperactivation As A Driver Of Radiotherapy Resistance And Suppressed Antitumor Immunity In Head And Neck Squamous Cell Carcinoma, Rutulkumar Patel, Kalil Saab, Lixia Luo, Yan Ma, Rashid Abdullah Osman, Nerissa T Williams, Jeffrey Everitt, Maciej J Zelazowski, Patricia Castro, William K Decker, William H Hudson, Jeffrey N Myers, Vlad C Sandulache, Mitchell J Frederick, Yvonne M Mowery, David G Kirsch

Faculty, Staff and Students Publications

Purpose: Alterations in the KEAP1/NFE2L2 (NRF2)/CUL3 pathway occur in ∼20% of human head and neck squamous cell carcinomas (HNSCC) and are associated with resistance to standard-of-care therapy. However, this pathway's role in radiotherapy resistance in HNSCC has not been well studied.

Experimental design: We generated genetically engineered mouse models and developed primary murine cancer cell lines harboring mutations commonly observed in human HNSCC, including inducible activation of PIK3CA and deletion of Trp53, with or without Keap1 loss. Primary tumors were initiated via 4-hydroxytamoxifen injection ± the tobacco carcinogen benzo[a]pyrene (BAP) into the oral buccal mucosa. Tumors were analyzed by Western …

Phosphorylation At Serine 214 Correlates With Tau Seeding Activity In An Age-Dependent Manner In Two Mouse Models For Tauopathies And Is Required For Tau Transsynaptic Propagation, Pablo Martinez, Nur Jury-Garfe, Henika Patel, Yanwen You, Abigail Perkins, Yingjian You, Audrey Lee-Gosselin, Ruben Vidal, Cristian A Lasagna-Reeves

Faculty, Staff and Students Publications

Background

Tau aggregation and propagation are hallmark features of Alzheimer's disease and related tauopathies. The molecular identity and post-translational modifications that contribute to tau seeding activity remain incompletely understood.

Objective

To characterize the temporal dynamics of tau seeding activity and identify specific phosphorylated tau species associated with tau propagation in vivo.

Methods

We profiled tau seeding activity using a FRET-based biosensor cell line and correlated it with the abundance of phospho- and conformational tau species in two transgenic mouse models of tauopathy (P301S-1N4R and P301S-0N4R). Immunohistochemistry and subcellular fractionation were used to examine the spatial distribution of tau species. Functional …

Systematic Targeting Of Gd2-Positive Neuroblastoma Tumors With A Photooncolytic Phage Nanovector Platform, Suleman Khan Zadran, Nicola Facchinello, Piergiuseppe De Rosa, Roberto Saporetti, Paolo Emidio Costantini, Luca Ulfo, Michela Nigro, Annapaola Petrosino, Lucia Pappagallo, Sara Aloisi, Giorgio Milazzo, Zainul Abe Din, Alberto Rigamonti, Leonardo Flora, Martina Santulli, Leonardo Cimadom, Giampaolo Zuccheri, Mattia Zangoli, Manuele Di Sante, Matteo Di Giosia, Francesca Di Maria, Roberto Bernardoni, Eveline Barbieri, Matteo Calvaresi, Alberto Danielli, Giovanni Perini

Faculty, Staff and Students Publications

Disialoganglioside-GD2 is a key molecular target for Neuroblastoma (NB) immunotherapy based on the employment of GD2-targeting antibodies. However, about 50% of treated patients can experience tumor relapse due to limited immune-mediated cytotoxicity and poor antibody penetration into tumors. To address this problem, a tumor-penetrating photo-oncolytic phage nanovector platform is genetically and chemically developed that selectively targets GD2-expressing NB cells. The phage bioconjugates, functionalized with different photosensitizers, result in specific and selective oncolysis of GD2-positive NB cells upon light irradiation, without affecting GD2-negative ones. The photo-oncolytic phage vectors are shown to deeply penetrate into GD2-positive tumor spheroids in vitro, and to …

Tigit Affects Car Nk-Cell Effector Function In The Solid Tumor Microenvironment By Modulating Immune Synapse Strength, Ishwar Navin, Matthew Dysthe, Prashant S Menon, Corrine Baumgartner, Tim Sauer, Navin Varadarajan, Robin Parihar

Faculty, Staff and Students Publications

Therapies using NK cells that express chimeric antigen receptors (CAR-NK) have been successfully employed against hematologic malignancies. However, solid tumors resist CAR-NKs partly by enriching tumor microenvironments with ligands for NK cell inhibitory receptors. Although the NK inhibitory receptor T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) has been implicated in impaired antitumor activity of endogenous NK cells, the consequences of TIGIT expression on engineered CAR-NKs have not been explored. To address this gap, we compared TIGIT-expressing and TIGIT-deleted human CAR-NKs targeting the GD2 solid tumor antigen in tumor immune microenvironment co-cultures and in vivo tumor immune …

Liver-Specific Expression Of Hiv-1 Viral Protein R Causes Hepatic Steatosis And Glucose Intolerance In Male Mice, Neeti Agarwal, Pradip Saha, Claudia E Ramirez Bustamante, Sean M Hartig, Mark A Herman, Ashok Balasubramanyam, Jordan E Lake

Faculty, Staff and Students Publications

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized in people with HIV (PWH), with both HIV and antiretroviral therapy contributing to liver damage and glucose intolerance. However, the role of viral proteins derived from reservoirs in this process remains unclear.

Methods: Adeno-associated virus (AAV) constructs encoding a control protein or HIV-1 viral protein R (Vpr) driven by the thyroxine-binding globulin promoter were administered to male mice (n = 5 per group) fed regular chow or a high-fat diet (HFD). Young adult mice underwent intraperitoneal glucose tolerance testing and magnetic resonance imaging, followed by euthanasia. Liver and adipose tissues …

Enhanced Control Of Liposomal Drug Release By Drug-Aptamer Complexes, Xiangang Huang, Yang Li, Matthew Torre, Rachelle Shao, Wei Zhang, Zihan Wang, Daniel S Kohane, Christopher B Weldon

Duncan NRI Faculty and Staff Publications

Conventional diffusion-controlled drug delivery systems (DDS) can have undesirable initial burst release, leading to potential systemic toxicity, and the rate of basal release can deplete content, shortening the duration of effect. Here, it is hypothesized that conventional drug delivery systems-using liposomes as an example-can be enhanced by incorporation of an aptamer that binds specifically to the encapsulated drug. Affinity of the aptamer to the drug within liposomes (Lipo-Apt) would slow release. It is demonstrated that this approach works with a range of relatively small and hydrophilic molecules, including tetrodotoxin (TTX), serotonin (Ser), and kanamycin (Kan). The in vivo utility of …

Unveiling Social Media Content Related To Adhd Treatment: Machine Learning Study Using X'S Posts Over 15 Years, Alba Gómez-Prieto, Alejandra Mercado-Rodriguez, Juan Pablo Chart-Pascual, Cesar I Fernandez-Lazaro, Francisco J Lara-Abelenda, María Montero-Torres, Claudia Aymerich, Javier Quintero, Melchor Alvarez-Mon, Ana Gonzalez-Pinto, Cesar A Soutullo, Miguel Angel Alvarez-Mon

Faculty, Staff and Student Publications

No abstract provided.

Decorin Evokes A Pro-Lysosomal Pathway In Lymphatic Endothelial Cells, Gabriel J. Pascal, Dipon K. Mondal, Sadie Kim, Christopher Xie, Devanarayanan Siva Sankar, Jörn Dengjel, Renato V. Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The lymphatic system is critical to the body's immune and circulatory system, and lymphangiogenesis, the development of new lymphatic vessels from pre-existing ones, is a significant process capitalized upon by cancer during tumorigenesis. Decorin is a small leucine-rich proteoglycan which we have previously shown to be anti-tumorigenic and a suppressor of lymphangiogenesis. We have also shown that decorin exercises its anticancer properties through its ability to evoke autophagy. Through a comprehensive and unbiased proteomic analysis, we explored the implications of decorin exposure on protein expression within mouse lymphatic endothelial cells. We discovered that decorin enriches several protein pathways, notably proteasomal …

Cookie-Pro: Covalent Inhibitor Binding Kinetics Profiling On The Proteome Scale, Hanfeng Lin, Bin Yang, Lang Ding, Yen-Yu Yang, Matthew V Holt, Sung Yun Jung, Bing Zhang, Meng C Wang, Jin Wang

Faculty, Staff and Students Publications

Covalent inhibitors are an emerging class of therapeutics, but methods to comprehensively profile their binding kinetics and selectivity across the proteome have been limited. Here we introduce COOKIE-Pro (COvalent Occupancy KInetic Enrichment via Proteomics), an unbiased method for quantifying irreversible covalent inhibitor binding kinetics on a proteome-wide scale. COOKIE-Pro uses a two-step incubation process with mass spectrometry-based proteomics to determine kinact and KI values for covalent inhibitors against both on-target and off-target proteins. We validated COOKIE-Pro using BTK inhibitors spebrutinib and ibrutinib, accurately reproducing known kinetic parameters and identifying both expected and unreported off-targets. The method revealed that …

Engineered Exosomes With Krasg12d Specific Sirna In Pancreatic Cancer: A Phase I Study With Immunological Correlates, Valerie S Kalluri, Brandon G Smaglo, Krishnan K Mahadevan, Michelle L Kirtley, Kathleen M Mcandrews, Mayela Mendt, Sujuan Yang, Ana S Maldonado, Hikaru Sugimoto, Maria E Salvatierra, Luisa M Solis Soto, Cara Haymaker, Rick Finch, Mihai Gagea, Adam C Fluty, Steven J Ludtke, J Jack Lee, Abhinav K Jain, Gauri Varadhachary, Rachna T Shroff, Anirban Maitra, Elizabeth Shpall, Shubham Pant, Raghu Kalluri

Faculty, Staff and Students Publications

Oncogenic KRAS is amongst the key genetic drivers for initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC). Here, we show that engineered exosomes with KrasG12D specific siRNA (iExoKrasG12D) reveal a biodistribution in pancreas with negligible toxicity in preclinical studies in mice and Rhesus macaques. Clinical testing of iExoKrasG12D in the iEXPLORE (iExoKrasG12D in Pancreatic Cancer) Phase I study employed a non-randomized single-arm classical 3 + 3 dose escalation design (Phase Ia), followed by an accelerated titration design (Phase Ib) (NCT03608631). The primary outcomes included safety, tolerability and target engagement, and the secondary outcomes aimed to assess disease control. …

Real-World Use Of Classic And Non-Classic Psychedelics In Hispanic/Latino Adults With Obsessive-Compulsive Disorder: International Findings From The Latino Study, David S Mathai, Jill O Robinson, Kevin Wagner, Logan Neitzke-Spruill, Dayan Berrones, Jacey L Anderberg, Renee M Frederick, Vanessa Zavala Cruz, Josselyn S Muñoz, Latin American Trans-Ancestry Initiative For Ocd Genomics, Brazilian Obsessive-Compulsive Spectrum Disorder Working Group;, Carolyn I Rodriguez, Lynnette A Averill, James J Crowley, Eric A Storch, Amy L Mcguire

Center for Medical Ethics and Health Policy Staff Publications

Objective: Despite growing research on the potential mental health benefits of psychedelics, there has been limited study of these drugs in populations with obsessive-compulsive disorder (OCD) and with Hispanic and Latin American (H/L) ancestry.

Methods: Demographic and clinical assessments were conducted as part of the Latin American Trans-ancestry Initiative for OCD genomics (LATINO) Study in H/L participants with OCD living throughout the Americas. Self-reported data on the prevalence of naturalistic psychedelic use and associated outcomes on OCD symptoms were collected in a subsample of 2,639 adults. Descriptive statistics and regression analyses were used to assess psychedelic use, predictors of use, …

Artificial Intelligence-Enabled Automated Analysis Of Transmission Electron Micrographs To Evaluate Chemotherapy Impact On Mitochondrial Morphology In Triple Negative Breast Cancer, Argenis Arriojas, Mokryun L Baek, Mariah J Berner, Jiaqi Wang, Joseph Duraisingh, Alexander Zhurkevich, Antentor Othrell Hinton, Matthew D Meyer, Lacey E Dobrolecki, Michael T Lewis, Kourosh Zarringhalam, Gloria V Echeverria

Faculty, Staff and Students Publications

Advancements in transmission electron microscopy (TEM) have enabled in-depth studies of biological specimens, offering new avenues to large-scale imaging experiments with subcellular resolution. Mitochondrial structure is of growing interest in cancer biology due to its crucial role in regulating the multi-faceted functions of mitochondria. We and others have established the crucial role of mitochondria in triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer with limited therapeutic options. Building upon our previous work demonstrating the regulatory role of mitochondrial structure dynamics in metabolic adaptation and survival of chemotherapy-refractory TNBC cells, we sought to extend those findings to a large-scale …

Dworf Gene Therapy Improves Cardiac Calcium Handling And Mitochondrial Function, Omar Brito-Estrada, Yasuhide Kuwabara, Aaron M Gibson, Keira R Hassel, Michael L Kamradt, Joseph P Verry, N Scott Blair, Michael J Bround, Jiuzhou Huo, Jeffery D Molkentin, Catherine A Makarewich

Faculty, Staff and Students Publications

Background: Calcium (Ca2+) dysregulation is a hallmark of heart failure, impairing excitation-contraction coupling and contributing to pathological remodeling. The sarco/endoplasmic reticulum Ca2+ ATPase isoform 2a (SERCA2a) mediates Ca2+ reuptake into the sarcoplasmic reticulum (SR) during diastole, but its activity declines in failing hearts. DWORF (dwarf open reading frame), a newly identified cardiac microprotein, enhances SERCA2a activity and improves cardiomyocyte Ca2+ cycling and contractility. SR Ca2+ release also influences mitochondrial metabolism and ATP production. Here, we investigated whether DWORF overexpression improves SR Ca2+ handling, augments mitochondrial Ca2+ signaling, and protects against heart failure progression.

Methods: Transgenic and adeno-associated virus approaches were …