Medical Specialties Commons^™

Diagnosing Acute Compartment Syndrome: A Surgical Emergency, Kallin J. Austin, Lara Laughrey, Marco Trevino, Eric Liou, Matthew Hazel, Brody Harn

Annual Research Symposium

Determine best practices for diagnosing acute compartment syndrome in the lower limb by comparing the sensitivity and specificity of commonly use techniques.

Development Of A Protocol For Obtaining Biological Samples For Genetic Testing From Remote Individuals, Noah R. Schultz, Brandon J. Burger, Jacob Warner, Alfred Amendolara, Jameson Williams, Molly Henley, Layla Risdon, Alessandra Maisie Rivera, Amanda Page, Millicent Jiang, Denisse Castaneda, Garret Phillips, John A. Kriak, Kyle B. Bills, David W. Sant

Annual Research Symposium

Pharmacogenomic sequencing allows individuals to learn more about how they will respond to certain medications but requires shipping of a biological sample. One complication of sending biological samples to remote laboratories is stability. Blood generally yields sufficient quantities of high-quality DNA but requires a clinic visit. Saliva and buccal swabs are routinely used for DNA extractions, but the DNA quality is notoriously low due to the presence of bacteria in the mouth. Additionally, elderly individuals have difficulty producing enough saliva for testing, and the tubes contain several milliliters of liquid and shipping requires special considerations. Dried blood spot cards, which …

Dna Extraction Method Development For Solid Tissues, Ryan Powers, Noah R. Schultz, Brandon J. Burger, John Dougherty Jr., Ezenna Obilor, Alexander Ruiz, Corwin Frey, Nathaniel Hill, Lara Laughrey, Patrick Tanner Brain, Sara Mcmahon, Parker Feltner, Steven Tung, Daoud Sajady, Elden Jenkins, Julian Jarquin, Serin Baker, Aaron Andrews, John A. Kriak, Kyle B. Bills, David W. Sant

Annual Research Symposium

Although germline variation testing is traditionally performed using DNA obtained from blood or other liquid samples, determining somatic variation in cancer samples requires DNA extraction directly from tissues. Additionally, epigenetic markers, such as 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are tissue-specific and change in selected disease states. However, several substances present in tissues are known to inhibit downstream reactions, including polymerase chain reaction PCR). For this project, we are assessing the quantity and quality of DNA obtained from extractions of various vital organs using 30 different commercially available DNA extraction kits to determine optimal kits for each tissue.

Investigating The Genetics Of Chronic Intractable Migraine With Reactive Hypoglycemia, C Yvonne Russell, Jacob Warner, Brandon J. Burger, Jordan Cutshall, Naeel Uddin, Patrick Tanner Brain, Alessandra Maisie Rivera, Braden Cunningham, Kailee Edwards, Katie Beechay, Luke Sanders, Zachary Ta, John A. Kriak, David W. Sant, Kyle B. Bills

Annual Research Symposium

Migraines affect roughly 1-in-6 males and 1-in-5 females in the United States. Of these, approximately 5-30% experience intractable migraines, or migraines resistant to abortive treatments. Despite this large population, relatively little is known about intractable migraines compared to other types of migraines. Our recent work indicates that reactive hypoglycemia is common among these individuals. Additionally, empirical evidence suggests that individuals in families with chronic intractable migraines are more likely to have the same condition than people of the general population, suggesting a possible genetic link between both migraines and metabolic abnormalities. Previous Genome Wide Association Studies (GWAS) have found several …

Investigating The Role Of Chaos In Minimizing Tumor Growth, Maxwell Geiger

Annual Research Symposium

Chaos is a type of motion found in mathematical systems that is highly sensitive to initial conditions. While many biological systems described in literature have been analyzed for the presence of chaotic dynamics, there are still many that are yet to be discovered. The goal of this project is to reassess Itik and Banks’ discovery of chaotic behavior in their population dynamics model of cancer growth. Once chaotic behavior is confirmed, we want to investigate how chaos could possibly be controlled to minimize tumor growth and discover novel treatments for cancer patients.

Late Cardiotoxicity From The Tyrosine Kinase Inhibitor, Dasatinib: Pleural Effusions, Pulmonary Arterial Hypertension, And Right Heart Failure, Mark Jay Zucker, Andrew M. Zucker

The VAD Journal

Despite the remarkable progress made over the past few decades in the management of patients with both solid and hematologic malignancies, radiation- and chemotherapy-related cardiotoxicity remains an ongoing problem. This is true even for newer highly targeted therapies, including tyrosine kinase inhibitors (TKIs). This report presents a case of late/severe right heart dysfunction secondary to pulmonary hypertension, developed after ten years of therapy with dasatinib. We also review the history of this known, but often unrecognized, and potentially reversible complication, and we suggest treatment options. Additionally, this case highlights the remarkable effectiveness of TKIs in patients with chronic myelogenous leukemia …

The National Status Of Pharmacists’ Ability To Prescribe Hormonal Contraceptives, Aleese Smith, Urvi Patel, Alexandra Arledge, Josie Young, Erin Johanson

Annual Research Symposium

The scope of practice for pharmacists first expanded in California and Oregon with the ability to prescribe hormonal contraceptives to patients in their communities. Since 2016, over 33 states now allow for pharmacist prescribing of birth control in their pharmacy practice laws.

90% of Americans live within 5 miles of a retail pharmacy, making community pharmacies an accessible resource who may otherwise be unable to access contraceptives. The gap in care experienced by certain patient populations is now being filled by pharmacists with their ability to prescribe birth control.

Conceptualizing Care Partners' Burden, Stress, And Support For Reintegrating Veterans: A Mixed Methods Study, Nicholas A. Rattray, Mindy Flanagan, Allison Mann, Leah Danson, Ai-Nghia Do, Diana Natividad, Katrina Spontak, Gala True

School of Medicine Faculty Publications

BACKGROUND: People who support Veterans as they transition from their military service into civilian life may be at an increased risk of psychological distress. Existing studies focus primarily on paid family caregivers, but few studies include spouses and informal non-family "care partners." We sought to identify key challenges faced by care partners of Veterans with invisible injuries. METHODS: Semi-structured interviews were conducted with 36 individuals involved in supporting a recently separated US military Veteran enrolled in a 2-year longitudinal study. CPs completed validated measures on perceived stress, caregiving burden, quality of their relationship, life satisfaction, and flourishing. Independent -tests were …

Risk Factors Associated With Poor Outcomes After Quadriceps Tendon Repair, Carlo Coadonato, Neel K. Patel, John Hayden Sonnier, Gregory Connors, Matthew Sabitsky, Emma Johnson, Donald W. Mazur, Shyam Brahmabhatt, Kevin Freedman

Rothman Institute Papers

Background:

Ruptures of the quadriceps tendon present most frequently in older adults and individuals with underlying medical conditions.

Purpose:

To examine the relationship between patient-specific factors and tear characteristics with outcomes after quadriceps tendon repair.

Study Design:

Case-control study; Level of evidence, 3.

Methods:

A retrospective review was conducted on all patients who underwent quadriceps tendon repair between January 1, 2016, and January 1, 2021, at a single institution. Patients <18 years and those with chronic quadriceps tendon tears (>6 weeks to surgery) were excluded. Information was collected regarding patient characteristics, presenting symptoms, tear characteristics, physical examination findings, and postoperative outcomes. Poor outcome was defined as a need for …

Cancergpt For Few Shot Drug Pair Synergy Prediction Using Large Pretrained Language Models, Tianhao Li, Sandesh Shetty, Advaith Kamath, Ajay Jaiswal, Xiaoqian Jiang, Ying Ding, Yejin Kim

Faculty, Staff and Student Publications

Large language models (LLMs) have been shown to have significant potential in few-shot learning across various fields, even with minimal training data. However, their ability to generalize to unseen tasks in more complex fields, such as biology and medicine has yet to be fully evaluated. LLMs can offer a promising alternative approach for biological inference, particularly in cases where structured data and sample size are limited, by extracting prior knowledge from text corpora. Here we report our proposed few-shot learning approach, which uses LLMs to predict the synergy of drug pairs in rare tissues that lack structured data and features. …

Alcohol Impairs Bioenergetics And Differentiation Capacity Of Myoblasts From Simian Immunodeficiency Virus-Infected Female Macaques, Danielle E. Levitt, Brianna L. Bourgeois, Keishla M. Rodríguez-Graciani, Patricia E. Molina, Liz Simon

School of Graduate Studies Faculty Publications

Alcohol misuse and HIV independently induce myopathy. We previously showed that chronic binge alcohol (CBA) administration, with or without simian immunodeficiency virus (SIV), decreases differentiation capacity of male rhesus macaque myoblasts. We hypothesized that short-term alcohol and CBA/SIV would synergistically decrease differentiation capacity and impair bioenergetic parameters in female macaque myoblasts. Myoblasts from naïve (CBA−/SIV−), vehicle [VEH]/SIV, and CBA/SIV (N = 4–6/group) groups were proliferated (3 days) and differentiated (5 days) with 0 or 50 mM ethanol (short-term). CBA/SIV decreased differentiation and increased non-mitochondrial oxygen consumption rate (OCR) versus naïve and/or VEH/SIV. Short-term alcohol decreased differentiation; increased maximal and non-mitochondrial …

Differences In Spine Growth Potential For Sanders Maturation Stages 7a And 7b Have Implications For Treatment Of Idiopathic Scoliosis, Yusuke Hori, Burak Kaymaz, Luiz Carlos Almeida Da Silva, Kenneth J. Rogers, Petya K. Yorgova, Peter G. Gabos, Suken Shah, Md

Department of Orthopaedic Surgery Faculty Papers

Purpose
This study aimed to clarify the differences in spine and total body height growth and curve progression between Sanders maturation stage (SMS) 7A and 7B in patients with adolescent idiopathic scoliosis (AIS).

Methods
This retrospective case–control study involving patients with AIS at SMS 7 evaluated the differential gains in the spine (T1-S1) and total body height and curve progression between SMS 7A and 7B. A validated formula was used to calculate the corrected height, accounting for height loss due to scoliosis. A multivariable non-linear and logistic regression model was applied to assess the distinct growth and curve progression patterns …

Comparison Of Thulium Fiber Laser Versus Holmium Laser In Ureteroscopic Lithotripsy: A Meta-Analysis And Systematic Review, Xiaoyu Tang, Shaojie Wu, Zhilong Li, Du Wang, Cheng Lei, Tongzu Liu, Xinghuan Wang, Sheng Li

Faculty, Staff and Student Publications

OBJECTIVES: To compare the efficacy and safety of thulium fiber laser (TFL) to holmium: YAG (Ho: YAG) laser in ureteroscopic lithotripsy for urolithiasis.

METHODS: PubMed, Web of Science, Embase, CENTRAL, SinoMed, CNKI database, VIP and Wanfang Database were systematically searched for all relevant clinical trials until September 2023. References were explored to identify the relevant articles. Meta-analysis was carried out for the retrieved studies using RevMan5.4.1 software, and the risk ratio, mean difference and 95% confidence interval were expressed. Statistical significance was set at p < 0.05. The main outcomes of this meta-analysis were stone-free rate (SFR), perioperative outcomes and intraoperative or postoperative complications.

RESULTS: Thirteen studies, including 1394 patients, were included. According to the results of pooled analysis, …

Correction: Neural Correlates Of Automatic Emotion Regulation And Their Association With Suicidal Ideation In Adolescents During The First 90-Days Of Residential Care, Matthew Dobbertin, Karina S Blair, Joseph Aloi, Sahil Bajaj, Johannah Bashford-Largo, Avantika Mathur, Ru Zhang, Erin Carollo, Amanda Schwartz, Jaimie Elowsky, J L Ringle, Patrick Tyler, R James Blair

Faculty, Staff and Student Publications

No abstract provided.

The Frequency Of Pathogenic Variation In The All Of Us Cohort Reveals Ancestry-Driven Disparities, Eric Venner, Karynne Patterson, Divya Kalra, Marsha M Wheeler, Yi-Ju Chen, Sara E Kalla, Bo Yuan, Jason H Karnes, Kimberly Walker, Joshua D Smith, Sean Mcgee, Aparna Radhakrishnan, Andrew Haddad, Philip E Empey, Qiaoyan Wang, Lee Lichtenstein, Diana Toledo, Gail Jarvik, Anjene Musick, Richard A Gibbs

Faculty, Staff and Students Publications

Disparities in data underlying clinical genomic interpretation is an acknowledged problem, but there is a paucity of data demonstrating it. The All of Us Research Program is collecting data including whole-genome sequences, health records, and surveys for at least a million participants with diverse ancestry and access to healthcare, representing one of the largest biomedical research repositories of its kind. Here, we examine pathogenic and likely pathogenic variants that were identified in the All of Us cohort. The European ancestry subgroup showed the highest overall rate of pathogenic variation, with 2.26% of participants having a pathogenic variant. Other ancestry groups …

P90rsk Pathway Inhibition Synergizes With Cisplatin In Tmem16a Overexpressing Head And Neck Cancer, Abdulkader Yassin-Kassab, Suman Chatterjee, Nayel Khan, Nathaniel Wang, Vlad C Sandulache, Eric H-B Huang, Timothy F Burns, Umamaheswar Duvvuri

Faculty, Staff and Students Publications

Head and neck squamous cell carcinoma (HNSCC) constitutes one of the most common types of human cancers and often metastasizes to lymph nodes. Platinum-based chemotherapeutic drugs are commonly used for treatment of a wide range of cancers, including HNSCC. Its mode of action relies on its ability to impede DNA repair mechanisms, inducing apoptosis in cancer cells. However, due to acquired resistance and toxic side-effects, researchers have been focusing on developing novel combinational therapeutic strategies to overcome cisplatin resistance. In the current study, we identified p90RSK, an ERK1/2 downstream target, as a key mediator and a targetable signaling node against …

Uterine Leiomyomata As A Cause Of Abdominal Compartment Syndrome In The Postpartum Period, Mason Hui, Baha Sibai, Alvaro Montealegre, Mateo G Leon

Faculty, Staff and Student Publications

Uterine leiomyomas are common benign smooth muscle tumors that often occur during the reproductive years. Although many cases may not result in significant complications, negative pregnancy outcomes have been associated with the size and location of the fibroids. Degeneration of fibroids can occur as early as the late first trimester when they undergo significant volumetric growth, contributing to pain during pregnancy. While myomectomy is typically avoided during pregnancy, conservative management with anti-inflammatory medications may be effective. Surgical removal or preterm delivery may be necessary if symptoms persist. Abdominal compartment syndrome (ACS) is a rare condition characterized by sustained elevated intra-abdominal …

Periacetabular Osteotomy: An Analysis Of Social Media To Determine The Most Common Questions Asked By The Periacetabular Osteotomy Population, John M. Gaddis, Bretton Laboret, Ryan Bialaszewski, Elizabeth Bergman, Jenny Lacross, Edward P. Mulligan, Joel Wells

School of Medicine Publications

Background: The Bernese Periacetabular Osteotomy (PAO) has become a popular surgery for fixing development dysplasia of the hip, yet the most common concerns of the PAO population remains ambiguous. The aim of this study was to investigate Facebook, Instagram and Twitter to further understand what the most common preoperative and postoperative questions patients undergoing PAO are asking. We hypothesized most questions would be asked by patients in the preoperative timeframe with regards to education surrounding PAO surgery.

Methods: Facebook, Instagram and Twitter were queried consecutively from February 1, 2023 to November 23, 2011. Facebook was searched for the two most …

Fragmenting Projectiles: A Case Report And Literature Review Of The G2 Radically Invasive Projectile, Matthew Bernard, Christine M. Dahlhausen, Andrew M. Kirk, Andrew Bernard

School of Medicine Publications

Innovations in projectile design present unique challenges for trauma surgeons when treating gunshot victims. The G2 Radically Invasive Projectile (G2 Research, Winder, Georgia, USA) (G2RIP) is a frangible, rapidly expanding bullet resulting in a distinct pattern of injury consisting of diffuse hemorrhage with multicavity trauma as well as unique radiographic features of the projectile. To efficiently manage patients injured by the G2RIP, trauma surgeons must be aware of these distinct characteristics, and of previous patterns in effective management such as liberal damage control and extensive use of CT. Understanding previous presentation and management of patients injured by the G2RIP can …

The Effect Of Sirolimus Immunosuppression On Cardiovascular Outcomes In Liver Transplantation, Jason Ho, Zach Breslin, Lauren Lally, Dina Halegoua-De Marzio, Danielle M. Tholey

Division of Gastroenterology and Hepatology Faculty Papers

Introduction: Non-alcoholic steatohepatitis (NASH) is a rising cause of liver transplantation and is linked to higher rates of cardiovascular complications. The aim of this study was to evaluate the risk of post-transplant cardiac events in patients with NASH that were exposed to sirolimus (SRL) vs. calcineurin-inhibitor (CNI) immunosuppression. Methods: We retrospectively reviewed all adult liver transplant recipients at our institution between 2002 and 2020. Subjects were grouped based on immunosuppressive regimen. We also analyzed the subgroup of patients with NASH as the primary indication for transplant, as well as a non-NASH subpopulation. The primary outcome measure was risk of major …

Description Of Cryptococcosis Following Sars-Cov-2 Infection: A Disease Survey Through The Mycosis Study Group Education And Research Consortium (Msg-19), Jeremey Walker, Todd Mccarty, Gerald Mcgwin, Eloy E Ordaya, Paschalis Vergidis, Luis Ostrosky-Zeichner, Mehriban Mammadova, Andrej Spec, Adriana M Rauseo, John Perfect, Julia Messina, Gabriel Vilchez, Rachel Mcmullen, Carolynn T Jones, Peter G Pappas

Faculty, Staff and Student Publications

BACKGROUND: Invasive fungal infections have been described throughout the COVID-19 pandemic. Cryptococcal disease after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been reported in several isolated case reports and 1 larger case series. We sought to describe cryptococcal infections following SARS-CoV-2 through establishing a database to investigate underlying risk factors, disease manifestations, and outcomes.

METHODS: We created a crowdsourced call for cases solicited through the Mycoses Study Group Education and Research Consortium, the Centers for Disease Control and Prevention Emerging Infectious Diseases Network, and infectious diseases Twitter groups. Data were collected in a web-based and secure REDCap …

Immunity From Nk Cell Subsets Is Important For Vaccine-Mediated Protection In Hpv+ Cancers, Madison P O'Hara, Ananta V Yanamandra, K Jagannadha Sastry

Faculty, Staff and Student Publications

High-risk human papillomaviruses (HPVs) are associated with genital and oral cancers, and the incidence of HPV+ head and neck squamous cell cancers is fast increasing in the USA and worldwide. Survival rates for patients with locally advanced disease are poor after standard-of-care chemoradiation treatment. Identifying the antitumor host immune mediators important for treatment response and designing strategies to promote them are essential. We reported earlier that in a syngeneic immunocompetent preclinical HPV tumor mouse model, intranasal immunization with an HPV peptide therapeutic vaccine containing the combination of aGalCer and CpG-ODN adjuvants (TVAC) promoted clearance of HPV vaginal tumors via induction …

Adaptation Of Chagas Disease Screening Recommendations For A Community Of At-Risk Hiv In The United States, Jesica Hayon, Sofia Lupo, Cristina Poveda, Kathryn M Jones, Qian Qian, Hulin Wu, Thomas P Giordano, Charles J Fleischmann, Caryn Bern, Jeffrey D Whitman, Eva H Clark

Faculty, Staff and Students Publications

Chagas disease (CD), caused by Trypanosoma cruzi, is underdiagnosed in the United States. Improved screening strategies are needed, particularly for people at risk for life-threatening sequelae of CD, including people with human immunodeficiency virus (HIV, PWH). Here we report results of a CD screening strategy applied at a large HIV clinic serving an at-risk population.

Deciphering Early-Stage Molecular Mechanisms Of Negative Pressure Wound Therapy In A Murine Model, Yu-Chiau Shyu, Ting-Shuo Huang, Hua-Sheng Chiu, Pavel Sumazin, Xin-Yu Lin, Po-Cheng Liao, Cai-Cin Liou, Fang-Chia Hsu, Jyuan-Siou Lin, Chih-Chin Hsu, Pang-Hung Hsu, Chi-Chin Sun, Chien-Tzung Chen

Faculty, Staff and Students Publications

Negative Pressure Wound Therapy (NPWT) is a commonly employed clinical strategy for wound healing, yet its early-stage mechanisms remain poorly understood. To address this knowledge gap and overcome the limitations of human trials, we establish an NPWT C57BL/6JNarl mouse model to investigate the molecular mechanisms involved in NPWT. In this study, we investigate the intricate molecular mechanisms through which NPWT expedites wound healing. Our focus is on NPWT's modulation of inflammatory immune responses and the concurrent orchestration of multiple signal transduction pathways, resulting in shortened coagulation time and reduced inflammation. Notably, we observe a significant rise in dickkopf-related protein 1 …

Abstinence Scoring Algorithms For Treatment Of Neonatal Opioid Withdrawal Syndrome (Nows), Brenton A. Maisel, Susan C. Adeniyi-Jones, Eric Selvage, Samuel Ng, Walter K. Kraft, Inna Chervoneva

Department of Pharmacology and Experimental Therapeutics Faculty Papers

OBJECTIVE: Chervoneva et al. (2020) developed an abbreviated score (sMNAS-9) derived from full modified Finnegan MOTHER NAS scale (MNAS) for evaluating severity of NOWS. We sought to develop NOWS treatment algorithms for clinical decision rules based on scores utilizing the shorter sMNAS.

STUDY DESIGN: This was a retrospective study of 373 infants with NOWS scored with MNAS and treated with morphine between 2007 and 2016. The infants were randomly split into training/test sets. The training set was used to derive optimized cutoff values for sMNAS-9 scores. The independent set evaluated the sMNAS-9 clinical decision rules based on full MNAS in …

Long Trimer-Immunization Interval And Appropriate Adjuvant Reduce Immune Responses To The Soluble Hiv-1-Envelope Trimer Base, Hongying Duan, Angela R Corrigan, Cheng Cheng, Andrea Biju, Christopher A Gonelli, Adam S Olia, I-Ting Teng, Kai Xu, Sijy O'Dell, Sandeep Narpala, Mike Castro, Leonid Serebryannyy, Jennifer Wang, Danealle K Parchment, Edward K Sarfo, Jelle Van Schooten, John-Paul Todd, Shuishu Wang, Darcy R Harris, Hui Geng, Alexander J Jafari, Vrc Production Program, Ruth A Woodward, Nicole A Doria-Rose, Kathryn E Foulds, Adrian B Mcdermott, Marit J Van Gils, Richard A Koup, Theodore C Pierson, Peter D Kwong, John R Mascola

Faculty, Staff and Student Publications

Soluble 'SOSIP'-stabilized HIV-1 envelope glycoprotein (Env) trimers elicit dominant antibody responses targeting their glycan-free base regions, potentially diminishing neutralizing responses. Previously, using a nonhuman primate model, we demonstrated that priming with fusion peptide (FP)-carrier conjugate immunogens followed by boosting with Env trimers reduced the anti-base response. Further, we demonstrated that longer immunization intervals further reduced anti-base responses and increased neutralization breadth. Here, we demonstrate that long trimer-boosting intervals, but not long FP immunization intervals, reduce the anti-base response. Additionally, we identify that FP priming before trimer immunization enhances antibody avidity to the Env trimer. We also establish that adjuvants Matrix …

A Small Molecule With Big Impact: Mrtx1133 Targets The Krasg12d Mutation In Pancreatic Cancer, Daoyan Wei, Liang Wang, Xiangsheng Zuo, Anirban Maitra, Robert S Bresalier

Faculty, Staff and Student Publications

KRAS mutations drive oncogenic alterations in numerous cancers, particularly in human pancreatic ductal adenocarcinoma (PDAC). About 93% of PDACs have KRAS mutations, with G12D (∼42% of cases) and G12V (∼32% of cases) being the most common. The recent approval of sotorasib (AMG510), a small-molecule, covalent, and selective KRASG12C inhibitor, for treating patients with non-small cell lung cancer represents a breakthrough in KRAS targeted therapy. However, there is a need to develop other much-needed KRAS-mutant inhibitors for PDAC therapy. Notably, Mirati Therapeutics recently developed MRTX1133, a small-molecule, noncovalent, and selective KRASG12D inhibitor through extensive structure-based drug design. MRTX1133 has demonstrated potent …

Sting Licensing Of Type I Dendritic Cells Potentiates Antitumor Immunity, Jian Wang, Suxin Li, Maggie Wang, Xu Wang, Shuqing Chen, Zhichen Sun, Xiubao Ren, Gang Huang, Baran D Sumer, Nan Yan, Yang-Xin Fu, Jinming Gao

Faculty, Staff and Student Publications

Stimulator of interferon genes (STING) is an immune adaptor protein that senses cyclic GMP-AMP (cGAMP) in response to self or microbial cytosolic DNA as a danger signal. STING is ubiquitously expressed in diverse cell populations including cancer cells with distinct cellular functions such as activation of type I interferons, autophagy induction, or triggering apoptosis. It is not well understood whether and which subsets of immune cells, stromal cells, or cancer cells are particularly important for STING-mediated antitumor immunity. Here using a polymeric STING-activating nanoparticle (PolySTING) with a “shock-and-lock” dual activation mechanism, we show type 1 conventional dendritic cell (cDC1) is …

Mutant P53 Protects Triple-Negative Breast Adenocarcinomas From Ferroptosis In Vivo, Denada Dibra, Shunbin Xiong, Sydney M Moyer, Adel K El-Naggar, Yuan Qi, Xiaoping Su, Elisabeth K Kong, Anil Korkut, Guillermina Lozano

Faculty, Staff and Student Publications

The TP53 tumor suppressor gene is mutated early in most of the patients with triple-negative breast cancer (TNBC). The most frequent TP53 alterations are missense mutations that contribute to tumor aggressiveness. Here, we used an autochthonous somatic TNBC mouse model, in which mutant p53 can be toggled on and off genetically while leaving the tumor microenvironment intact and wild-type for p53 to identify physiological dependencies on mutant p53. In TNBCs that develop in this model, deletion of two different hotspot p53R172H and p53R245W mutants triggers ferroptosis in vivo, a cell death mechanism involving iron-dependent lipid peroxidation. Mutant p53 protects cells …

Inter-Individual Variations In Circadian Misalignment-Induced Nafld Pathophysiology In Mice, Nobuya Koike, Yasuhiro Umemura, Hitoshi Inokawa, Isao Tokuda, Yoshiki Tsuchiya, Yuh Sasawaki, Atsushi Umemura, Naoko Masuzawa, Kazuya Yabumoto, Takashi Seya, Akira Sugimoto, Seung-Hee Yoo, Zheng Chen, Kazuhiro Yagita

Faculty, Staff and Student Publications

Pathological consequences of circadian misalignment, such as shift work, show considerable individual differences, but the lack of mechanistic understanding hinders precision prevention to prevent and mitigate disease symptoms. Here, we employed an integrative approach involving physiological, transcriptional, and histological phenotypes to examine inter-individual differences in pre-symptomatic pathological progression, preceding irreversible disease onset, in wild-type mice exposed to chronic jet-lag (CJL). We observed that CJL markedly increased the prevalence of hepatic steatosis with pronounced inter-individual differences. Stratification of individual mice based on CJL-induced hepatic transcriptomic signature, validated by histopathological analysis, pinpoints dysregulation of lipid metabolism. Moreover, the period and power of …