Digital Commons Network^™

Lung Adenocarcinoma Surfaceome Remodeling With Egfr Inhibitors Uncovers Placental Alkaline Phosphatase As A Target For Combination Therapy, Yihui Chen, Rongzhang Dou, Monica J Hong, Hanwen Xu, Jody Vykoukal, Ricardo A León-Letelier, Yining Cai, Soyoung Park, Ehsan Irajizad, Fu Chung Hsiao, Jennifer B Dennison, Edwin J Ostrin, Johannes F Fahrmann, Hiroyuki Katayama, Samir M Hanash

Faculty, Staff and Student Publications

Treatment of lung adenocarcinomas (LUADs) that exhibit activated epidermal growth factor receptor (EGFR) with EGFR tyrosine kinase inhibitors (TKIs) has limited efficacy. Assessment of the impact of EGFR TKI on the LUAD surfaceome remodeling reveals potential therapeutic targets. We identify placental type alkaline phosphatase (ALPP), which has restricted expression in normal tissues, among upregulated surface proteins following EGFR TKI treatment of both TKI sensitive as well as resistant cells. EGF treatment represses ALPP expression, whereas EGFR TKIs upregulate its expression through dephosphorylation and activation of FoxO3a, a transcriptional regulator that binds to the promoter region of ALPP. The combination of …

Low-Dimensional Signatures Of Neuronal Activity Associated With Long-Term Operant Conditioning In Aplysia, Sara Vanaki, Nicholas O Gonzalez, Curtis L Neveu, Yuto Momohara, Behnaam Aazhang, John H Byrne

Faculty, Staff and Student Publications

Operant conditioning is a form of learning in which a behavior is reinforced by reward. Operant conditioning has multiple temporal domains, ranging from short-term, lasting a few minutes, to long-term, persisting for at least 24 h. The extent to which short- and long-term operant conditioning memories rely on shared or separate neural mechanisms is poorly understood. Voltage-sensitive dye (VSD) imaging has been used previously to record the activity of a large number of neurons simultaneously in the buccal ganglion to measure changes in neuronal activity during short-term operant conditioning. We examined neuronal activity using VSD 24 h after operant conditioning …

Targeting Kinesin Family Member 20a Sensitizes Stem-Like Triple-Negative Breast Cancer Cells To Standard Chemotherapy, Yayoi Adachi, Weilong Chen, Cheng Zhang, Tao Wang, Nina Gildor, Rachel Shi, Haoyong Fu, Masashi Takeda, Qian Liang, Fangzhou Zhao, Hongyi Liu, Jun Fang, Jin Zhou, Hongwei Yao, Lianxin Hu, Shina Li, Lei Guo, Lin Xu, Ling Xie, Xian Chen, Chengheng Liao, Qing Zhang

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC), being both aggressive and highly lethal, poses a major clinical challenge in terms of treatment. Its heterogeneity and lack of hormone receptors or HER2 expression further restrict the availability of targeted therapy. Breast cancer stem cells (BCSCs), known to fuel TNBC malignancy, are now being exploited as a vulnerability for TNBC treatment. Here, we dissected the transcriptome of BCSCs and identified kinesin family member 20A (KIF20A) as a key regulator of BCSC survival and TNBC tumorigenesis. Genetic depletion or pharmacological inhibition of KIF20A impairs BCSC viability and tumor initiation and development in vitro and in vivo. …

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 …

Agpat2 Acts At The Crossroads Of Lipid Biosynthesis And Drp1-Mediated Er Morphogenesis, Yoshihiro Adachi, Mauricio Torres, Allen H Hunter, Woo Jung Cho, Meixia Pan, Xianlin Han, Guangwei Du, Ling Qi, Miho Iijima, Hiromi Sesaki

Faculty, Staff and Student Publications

The morphology of the endoplasmic reticulum (ER), characterized by central sheets and peripheral tubules, is controlled by membrane-shaping proteins. However, the role of lipids in ER morphogenesis remains elusive, despite the ER being the major site for lipid synthesis. Here, by examining the role of eighteen phosphatidic acid (PA)-generating enzymes in ER morphology, we identify lysophosphatidic acid acyltransferase 2 (AGPAT2) as a critical factor in mouse and human cells. AGPAT2 produces PA in the glycerophospholipid/triacylglycerol biosynthesis pathway, and its mutations cause congenital generalized lipodystrophy. We find that AGPAT2-generated PA drives ER tubulation through gene knockout, 3D structural analysis by FIB-SEM, …

Seed Amplification Of Msa Alpha-Synuclein Aggregates Preserves The Biological And Structural Properties Of Brain-Derived Aggregates, Fei Wang, Victor Banerjee, Carla Barria, Santiago Ramirez, Tyler Allison, Damian Gorski, Haley Evans, Quynh Nguyen, Danielle Harrison, Rabab Al-Lahham, Nicole De Gregorio Carbonell, Michelle Pinho, Sanne Kaalund, Jonas Folke, Susana Aznar, Luis Concha-Marambio, Mohd Ishtikhar, Venkata Kps Mallampalli, Sandra Pritzkow, Mohammad Shahnawaz, Matthew L Baker, Irina Serysheva, Claudio Soto

Faculty, Staff and Student Publications

Parkinson's disease (PD), Dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are characterized by the misfolding and aggregation of alpha-synuclein (αSyn). Compelling evidence showed that αSyn aggregates exist as distinct conformational strains in different synucleinopathies. Recently, we reported that the αSyn Seed Amplification Assay (αSyn-SAA) can amplify and distinguish αSyn strains from PD and MSA. In this study, we investigate whether MSA-seeded, SAA-amplified αSyn fibrils retain the biological and structural properties of the αSyn seeds present in MSA brains. We study the biological activities of both brain-derived and SAA-amplified αSyn aggregates using an αSyn "biosensor" cell model and …

Imaging Reactive Oxygen Species With L-012 Reveals Neutrophil Extracellular Trap Formation In Pancreatic Ductal Adenocarcinoma, Angisha Basnet, Kaitlyn M Landreth, Michael Sestito, Kristen Ranson, Seth T Gammon, David Piwnica-Worms, Brian A Boone, Tracy W Liu

Faculty, Staff and Student Publications

Neutrophils, key effector cells of the innate immune system, combat pathogens through mechanisms including the production of reactive oxygen species (ROS) and the release of neutrophil extracellular traps (NETs). While these responses are critical for host defense, prolonged elevation of ROS and dysregulated NETosis mediated by neutrophils have been implicated in autoimmune diseases, chronic inflammation, and cancer. In pancreatic ductal adenocarcinoma (PDAC), a highly aggressive and inflammatory malignancy, an increase in neutrophils infiltrating the tumor microenvironment promotes cancer progression and metastasis through increased ROS production and NET release. Using bioluminescence imaging with the reporter L-012 and NET assays, we assessed …

Actin Dysregulation Induces Neuroendocrine Plasticity And Immune Evasion: A Vulnerability Of Small Cell Lung Cancer, Yoojeong Seo, Shengzhe Zhang, Jinho Jang, Kyung-Pil Ko, Kee-Beom Kim, Yuanjian Huang, Dong-Wook Kim, Bongjun Kim, Gengyi Zou, Jie Zhang, Sohee Jun, Wonhong Chu, Nicole A Kirk, Ye Eun Hwang, Young Ho Ban, Shilpa S Dhar, Joseph M Chan, Min Gyu Lee, Charles M Rudin, Kwon-Sik Park, Jae-Il Park

Faculty, Staff and Student Publications

Small cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic options. Capping protein inhibiting regulator of actin dynamics (CRACD) that promotes actin polymerization, is frequently inactivated in SCLC. However, the role of CRACD loss in SCLC is unknown. Here we show that CRACD depletion drives neuroendocrine (NE) cell plasticity and immune evasion in SCLC. Mechanistically, CRACD inactivation disrupts actin organization, leading to suppression of Yap1-NOTCH signaling and subsequent NE gene upregulation. Simultaneously, CRACD loss drives EZH2-mediated histone methylation via nuclear actin disruption, leading to repression of MHC-I genes and depletion of CD8⁺ T cells. Consequently, CRACD-downregulated tumors exhibit …

Fgf13 Regulates Vgsc-Independent Cardiomyocyte Impulse Propagation Via Cx43 Trafficking, Lala Tanmoy Das, Mattia Malvezzi, Aravind R Gade, Maiko Matsui, Margaret Mckay, Eric Q Wei, Matea J Zelich, Keon Mazdisnian, Jared Kushner, Bi-Xing Chen, Isabella Distefano, Daniel Roybal, Lin Yang, Lisa Stoll, James C Lo, Marian Kalocsay, Fadi G Akar, Steven O Marx, Geoffrey S Pitt

Faculty, Staff and Student Publications

Background: FHF (fibroblast growth factor homologous factor) variants associate with arrhythmias. Although FHFs are best characterized as regulators of voltage-gated sodium channel (VGSC) gating, recent studies suggest broader, non-VGSC-related functions, including regulation of Cx43 (connexin 43) gap junctions and hemichannels, mechanisms that have generally been understudied or disregarded.

Methods: We assessed cardiac conduction and cardiomyocyte action potentials in mice with constitutive cardiac-specific Fgf13 ablation (cFgf13KO) while targeting Cx43 gap junctions and hemichannels pharmacologically. We characterized FGF13 regulation of Cx43 abundance and subcellular distribution. With proximity labeling proteomics, we investigated novel candidate mechanisms underlying FGF13 regulation of Cx43. …

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 …

Inhibition Of Clostridioides Difficile-Specific Dna Adenine Methyltransferase Cama By Analogs Of S‑Adenosyl‑L‑Methionine, Jujun Zhou, Youchao Deng, Dan Yu, Taraneh Hajian, Masoud Vedadi, Xing Zhang, Robert M Blumenthal, Rong Huang, Xiaodong Cheng

Faculty, Staff and Student Publications

Epigenetically targeted therapies, especially those inhibiting S-adenosyl-l-methionine (SAM)-dependent methylations of DNA, mRNA, and histones, have advanced rapidly in cancer treatment. However, these therapies remain underexplored for antibiotic development, despite the growing threat of antimicrobial resistance. Here, we screened a focused library of SAM analogs against the DNA adenine methyltransferase CamA specific to the enteric pathogen Clostridioides difficile. At the same time, we examined six other adenine methyltransferases, including two bacterial DNA methyltransferases and four human RNA methyltransferases having distinct RNA substrates. Compound 113 selectively inhibited CamA (IC50 = 0.15 μM). In addition, compound 67 inhibited Caulobacter crescentus CcrM …

Hif-2-Dependent Regulation Of Pthrp And Paraneoplastic Hypercalcemia In Aggressive Clear-Cell Renal Cell Carcinoma, Arijit Mal, Bingqing Xie, Zane Gray, Charlotte Small, Susmita G Ramanand, Yunpeng Gao, Vanina Toffessi Tcheuyap, Sashi Debnath, Alana Christie, Jeffrey Miyata, Brooklyn Jackson, Hua Zhong, Boning Gao, Jay Lohrey, Naim M Maalouf, Sangeetha M Reddy, John D Minna, Ivan Pedrosa, Xiankai Sun, Ram S Mani, Payal Kapur, James Brugarolas

Faculty, Staff and Student Publications

Renal cell carcinoma (RCC) patients with hypercalcemia (HC) have worse outcomes. HC often involves PTHrP, and the role of HIF-2 is incompletely understood. Leveraging RCC tumorgraft (TG) models of HC, which were characterized by tumor cell autonomous inflamatory/immune signatures, we show that HIF-2 inhibition with PT2399 frequently normalized calcium, downregulated circulating PTHrP and reduced HIF-2 binding to the PTHLH (PTHrP) promoter. Likely contributing to the selective induction of PTHrP in a subset of HIF-2-dependent tumors, the PTHLH locus was generally more accessible in TG(HC). However, PTHLH chromatin accessibility was grossly unaffected by PT2399, unlike elsewhere (including EPO locus in a …

Combining Pirfenidone With Mycophenolate Mofetil For Systemic Sclerosis-Related Interstitial Lung Disease (Scleroderma Lung Study Iii): An Investigator-Initiated, Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial, Dinesh Khanna, Cathie Spino, Donald P Tashkin, Elana J Bernstein, Jonathan Goldin, Eric C Kleerup, Airi Harui, Grace Ibrahim, Grace Hyun J Kim, Suiyuan Huang, Richard Mclain, Yi-Hsuan Tu, Vivek Nagaraja, Richard M Silver, Virginia D Steen, S Samuel Weigt, Joyce S Lee, Aryeh Fischer, Mary Beth Scholand, Jessica K Gordon, Paul F Dellaripa, Ivan O Rosas, Gary M Hunninghake, Marcin A Trojanowski, Robert W Simms, Jane E Dematte, Vivien M Hsu, Robyn T Domsic, Ganesh Raghu, Maureen D Mayes, Ryan D Boente, Michael D Roth

Faculty, Staff and Student Publications

Objective: Mycophenolate mofetil (MMF) can stabilize or improve lung function in systemic sclerosis-related interstitial lung disease (SSc-ILD). We hypothesized that combining MMF with pirfenidone (PFD) would produce a significantly more rapid and/or greater improvement in lung function.

Methods: A randomized (1:1), double-blind, placebo (PLA)-controlled phase 2 trial was conducted in SSc-ILD in which patients received PFD or PLA (801 mg three times daily) along with MMF (1,500 mg twice daily) for 18 months. The primary outcome was change in percent predicted forced vital capacity (FVC-%). Linear mixed-effects models assessed treatment differences in a modified intention-to-treat population.

Results: Only fifty-one of …

Revisiting Soluble Guanylate Cyclase Pharmacology: Additive Potential Of Stimulators And Activators, Alexandra Petraina, Mahmoud H Elbatreek, Christopher T Neullens, Theodora Saridaki, Vu Thao-Vi Dao, Rebecca D Szepanowski, Emil Martin, Wolfgang Sippl, Ana I Casas, Harald H H W Schmidt

Faculty, Staff and Student Publications

Nitric oxide (NO) is a key gasotransmitter that binds to soluble guanylate cyclase (sGC), thereby stimulating cGMP production. Under disease conditions, reactive oxygen species disrupt this signaling by either: (1) scavenging NO, or (2) promoting heme-free, NO-insensitive apo-sGC due to impaired heme incorporation or oxidative damage. To counteract these conditions, two pharmacological approaches have emerged: sGC stimulators, which allosterically enhance sGC sensitivity to low NO levels; and sGC activators, which directly activate apo-sGC (heme-free sGC) by binding to its empty heme pocket, inducing a conformation that mimics NO-bound sGC. Thus, sGC stimulators are thought to target only sGC. Instead, we …

Allogeneic Bone Marrow-Derived Mesenchymal Stem Cells For Parkinson's Disease: A Randomized Trial., Mya C Schiess, Jessika Suescun, Juan D Martinez-Lemus, Charles Green, Tia S Thomas, Mohammad Shahnawaz, Emily Tharp, Nikunj B Satani, Jerome G Saltarrelli, Christopher Adams, Marie-Francoise Doursout, Vanessa Thyne, Rula Abuamouneh, Elsa M Rodarte, Sean I Savitz, Timothy M Ellmore

Faculty, Staff and Student Publications

Background: Neuroinflammation contributes to Parkinson's disease (PD) progression and motor dysfunction. Allogeneic human mesenchymal stem cells (allo-hMSCs) may reduce neuroinflammation and improve motor symptoms.

Objectives: To evaluate the efficacy of repeated intravenous doses of 10 × 106/kg allo-hMSCs in improving motor symptoms in patients with PD (PwP).

Methods: In this phase 2, randomized, placebo-controlled trial (November 2020-July 2023), mild-to-moderate PwP received either three allo-hMSC infusions, one placebo followed by two allo-hMSC infusions, or three placebo infusions at 18-week intervals. Follow-up lasted 88 weeks. The primary outcome was a >70% posterior probability (PP) of a difference in the proportion of participants …

Tumor Intrinsic Mettl5 Modulates Atf4 Translation To Prevent T Cell-Induced Ferroptosis In Ovarian Cancer, Jiakai Hou, Cheng-Wei Ju, Nicholas A Egan, Yanjun Wei, Yunfei Wang, Minghao Dang, Tianyi Zhou, Leilei Shi, Ningbo Zheng, Si Chen, Ashley M Guerrero, Xiaofang Liang, Wanfu Wu, Areej Akhtar, Chitra Dhiman, Debanwita Roy Burman, Andro E Gerges, Mason D Flores, Han Li, Li-Sheng Zhang, Marleen Kok, Xiaobo Mao, Linghua Wang, Qin Feng, Yiwen Chen, Sanghoon Lee, Daniel J Mcgrail, Nidhi Sahni, Chuan He, Amir A Jazaeri, Weiyi Peng

Faculty, Staff and Student Publications

Poor clinical responses to immune checkpoint blockade (ICB) observed in ovarian cancer (OC) highlight an unmet need to understand the mechanisms driving immune evasion in this disease. To address this, an integrative analysis is conducted by combining in vitro genome‐wide immune screens, in vivo ICB screens, and clinical data mining, and METTL5 is identified as a crucial OC‐intrinsic factor that promotes immune resistance. Immunologically “cold” OC tumors and poor responders to ICB exhibit elevated METTL5 expression. Mechanistically, knocking out (KO) METTL5 in OC disrupts ATF4 translation by altering 18S rRNA m6A levels, leading to the downregulation of SLC7A11 and SLC3A2 …

Perceived Utility Of Genetic Carrier Screening In A Diverse Patient Population, Jack A Colleran, Meagan Choates, Syed Hashmi, Brittanie Shelton, Aranza Gonzalez Cendejas, Angela Haynes Burgess, Blair K Stevens

Faculty, Staff and Student Publications

Current reproductive guidelines call for offering expanded carrier screening (ECS) for genetic conditions. Currently available panels can include screening for carrier status of tens to hundreds of autosomal recessive and/or X-linked conditions. Clinical utility is based on alterations to reproductive decision-making, but study cohorts supporting the utility of ECS largely consist of individuals of European ancestry who are highly educated, of high income, and who often receive preconception counseling. There is a lack of research on the views of patients from diverse backgrounds. Therefore, we aimed to assess and compare perceptions of the utility of ECS and targeted carrier screening …

Kras Inhibition Activates An Actionable Cd24 "Do Not Eat Me" Signal In Pancreatic Cancer, Yongkun Wei, Minghui Liu, Er-Yen Yen, Jun Yao, Zhenzhen Xun, Phuoc T Nguyen, Xiaofei Wang, Zecheng Yang, Abdelrahman Yousef, Dean Pan, Yanqing Jin, Ching-Fei Li, Madelaine S Theardy, Jangho Park, Yiming Cai, Mitsunobu Takeda, Matthew Vasquez, Elizabeth M Park, David H Peng, Yong Zhou, Hong Zhao, Timothy P Heffernan, Andrea Viale, Huamin Wang, Stephanie S Watowich, Han Liang, Dan Zhao, Ronald A Depinho, Wantong Yao, Haoqiang Ying

Faculty, Staff and Student Publications

KRASG12C inhibitors (G12Ci) have produced encouraging, albeit modest and transient, clinical benefit in pancreatic ductal adenocarcinoma (PDAC). Identifying and targeting resistance mechanisms to G12Ci treatment is therefore crucial. To better understand the function of KRASG12C and possible G12Ci bypass mechanisms, we developed an autochthonous KRASG12C-driven PDAC model. Compared to the classical KRASG12D PDAC model, the G12C model exhibits slower tumor growth, yet similar histopathological and molecular features. Aligned with clinical experience, G12Ci treatment of KRASG12C tumors produced modest impact despite stimulating a ‘hot’ tumor immune microenvironment. Immunoprofiling revealed that CD24, a ‘don’t eat me’ signal, is significantly upregulated on cancer …

Evidence For Improved Dna Repair In The Long-Lived Bowhead Whale, Denis Firsanov, Max Zacher, Xiao Tian, Todd L Sformo, Yang Zhao, Gregory Tombline, J Yuyang Lu, Zhizhong Zheng, Luigi Perelli, Enrico Gurreri, Li Zhang, Jing Guo, Anatoly Korotkov, Valentin Volobaev, Seyed Ali Biashad, Zhihui Zhang, Johanna Heid, Alexander Y Maslov, Shixiang Sun, Zhuoer Wu, Jonathan Gigas, Eric C Hillpot, John C Martinez, Minseon Lee, Alyssa Williams, Abbey Gilman, Nicholas Hamilton, Ekaterina Strelkova, Ena Haseljic, Avnee Patel, Maggie E Straight, Nalani Miller, Julia Ablaeva, Lok Ming Tam, Chloé Couderc, Michael R Hoopmann, Robert L Moritz, Shingo Fujii, Amandine Pelletier, Dan J Hayman, Hongrui Liu, Yuxuan Cai, Anthony K L Leung, Zhengdong Zhang, C Bradley Nelson, Lisa M Abegglen, Joshua D Schiffman, Vadim N Gladyshev, Carlo C Maley, Mauro Modesti, Giannicola Genovese, Mirre J P Simons, Jan Vijg, Andrei Seluanov, Vera Gorbunova

Faculty, Staff and Student Publications

At more than 200 years, the maximum lifespan of the bowhead whale exceeds that of all other mammals. The bowhead is also the second-largest animal on Earth1, reaching over 80,000 kg. Despite its very large number of cells and long lifespan, the bowhead is not highly cancer-prone, an incongruity termed Peto’s paradox2. Here, to understand the mechanisms that underlie the cancer resistance of the bowhead whale, we examined the number of oncogenic hits required for malignant transformation of whale primary fibroblasts. Unexpectedly, bowhead whale fibroblasts required fewer oncogenic hits to undergo malignant transformation than human fibroblasts. …

Periostin Promotes Sarcoma Growth By Promoting Tumor-Associated Macrophage Migration And Differentiation, Jin-Fen Xiao, Kristin Ishaya, Emily Y Ko, Annaliese Fowler, Marina T Broz, Jlenia Guarnerio

Faculty, Staff and Student Publications

Soft-tissue sarcomas (STS) are characterized by abundant extracellular matrix (ECM) deposition, yet the functional contribution of specific ECM components remains poorly understood. In this study, we identify periostin (POSTN), a matricellular protein, as a regulator of sarcoma progression and the tumor immune microenvironment. Analysis of human sarcoma datasets revealed that high POSTN expression correlates with poor prognosis and elevated expression of ECM-related and myeloid cell–associated genes. In murine genetic models of sarcoma, tumors expressing high levels of Postn displayed enhanced expression of ECM genes and monocyte-recruiting cytokines. Functional silencing of Postnin vivo reduced tumor growth without altering tumor cell …

Prone Percutaneous Jungbluth For Reduction Of Irreducible Posterior Pelvic Ring Injuries: A Technical Trick, Joseph M Radley, Jonathan A Copp, Daniel S Gloekler, Jonathan G Eastman

Faculty, Staff and Student Publications

Unstable pelvic ring injuries represent a challenge due to the complex anatomy. Further, surgical access to the pelvic ring is altered by patient positioning in the supine versus prone position. Certain injury patterns present with the posterior pelvis in a fixed displaced position. These injuries can be exceedingly challenging to reduce from a supine position. In the prone position, these injuries can be reduced more directly with an open approach, but this is associated with wound healing complications. The technical trick herein demonstrated a successful technique utilizing a large Jungbluth clamp percutaneously applied to the posterior superior iliac spines with …

Efficacy Of Platelet Rich Plasma Versus Placebo For Improvement In Olfactory Function In Adults With Olfactory Dysfunction: A Systematic Review And Meta-Analysis, Ali B Jafar, Ghabrielle Almeida, Fatima Al Mousawi, Eric Delgado Rendon, Amber U Luong

Faculty, Staff and Student Publications

Background: Olfactory dysfunction significantly impairs quality of life. Conventional treatments such as corticosteroids and olfactory training offer limited and inconsistent efficacy. Platelet-rich plasma (PRP), a biologically active agent, has shown potential regenerative effects in olfactory neuroepithelium. This study systematically evaluates the efficacy of PRP compared to placebo in improving olfactory function.

Methods: A systematic review and meta-analysis was conducted according to PRISMA guidelines and was registered in PROSPERO (CRD 420251045079). The databases searched included PubMed, Scopus, Embase, Central, and Web of Science. Seven studies (four RCTs, three non-RCTs) involving 789 patients were included. Subjective and objective outcomes were extracted and …

Whipple Disease Initial Presentation As Supraclavicular Lymphadenopathy In A Patient With Rheumatoid Arthritis: A Diagnostic Challenge, Sara E Amin, Swati Gite, Audrey Wanger, Violeta Chavez, Jacob Armstrong, Beenu Thakral, Patricia Navarro, Jennifer Makhoul, Amer Wahed, Navneet Narula, Karan Saluja

Faculty, Staff and Student Publications

Whipple disease is a rare systemic disease caused by Tropheryma whipplei. It can present with a wide range of nonspecific symptoms that might overlap with underlying medical conditions, posing a diagnostic challenge. We present a 61-year-old man with a past medical history of rheumatoid arthritis and chronic inflammatory demyelinating polyneuropathy, who presented with persistent leukocytosis and supraclavicular lymphadenopathy. A positron emission tomography scan revealed hypermetabolic activity in the supraclavicular, abdominal, and pelvic lymph nodes along with a myocardial hypermetabolic lesion, concerning a lymphoproliferative disorder versus sarcoidosis. A supraclavicular lymph node excisional biopsy revealed complete architectural effacement by a diffuse foamy …

Reviewing Vascular Influences On Neuronal Migration, Cortical Development, And Neurodevelopmental Disorders: Focus On Autism, Adhd And Schizophrenia, Lalit K Ahirwar, Spiros L Blackburn, Devin W Mcbride, Peeyush Kumar T

Faculty, Staff and Student Publications

During cortical development, newly born neurons migrate radially or tangentially from their origin to expand the cortex. Simultaneously, neuron-derived factors support angiogenesis, and an elaborate network of blood cerebral vessels develops in the cortex. Traditionally, blood cerebral vessels were considered to support the growing cortex or migrating neurons by providing nutrients and oxygen. However, recent studies have shed light on Endothelial cells' influence on cortical development; they guide neuronal migration by providing molecular cues and structural support. Here, we review the current understanding of how CNS cerebral vessels support neurogenesis, neuronal migration, and the formation of the six-layer cortical structure …

Evaluation Of Renal Masses With Cest Mri: Protocol Optimization And Preliminary Results, Xiaojing Wang, Jochen Keupp, Ivan E Dimitrov, Ananth Madhuranthakam, Durga Udayakumar, Mahsa Taherzadeh, Emin Albayrak, Orson W Moe, Payal Kapur, Robert E Lenkinski, Ivan Pedrosa, Elena Vinogradov

Faculty, Staff and Student Publications

Purpose: This study investigates the application of CEST MRI in human kidneys, with the overarching goal of developing CEST MRI for renal mass characterization. Here, the focus is on the development of a protocol and the proof-of-principle evaluation of CEST for the characterization of clear cell renal cell carcinoma (ccRCC).

Methods: Ten healthy volunteers and five patients diagnosed with ccRCC underwent CEST MRI scans at 3 T. The sequence performance was characterized in healthy volunteers and tested using three saturation power levels, B1rms = 0.7, 1.2, and 1.6 μT. We compared the magnetization transfer ratio asymmetry (MTRasym) values at 1.0, …

Smart Spatial Omics (S2-Omics) Optimizes Region Of Interest Selection To Capture Molecular Heterogeneity In Diverse Tissues, Musu Yuan, Kaitian Jin, Hanying Yan, Amelia Schroeder, Chunyu Luo, Sicong Yao, Bernhard Dumoulin, Jonathan Levinsohn, Tianhao Luo, Jean R Clemenceau, Inyeop Jang, Minji Kim, Yunhe Liu, Minghua Deng, Emma E Furth, Parker Wilson, Anupma Nayak, Idania Lubo, Luisa Maren Solis Soto, Linghua Wang, Jeong Hwan Park, Katalin Susztak, Tae Hyun Hwang, Mingyao Li

Faculty, Staff and Student Publications

Spatial omics technologies have transformed biomedical research by enabling high-resolution molecular profiling while preserving the native tissue architecture. These advances provide unprecedented insights into tissue structure and function. However, the high cost and time-intensive nature of spatial omics experiments necessitate careful experimental design, particularly in selecting regions of interest (ROIs) from large tissue sections. Currently, ROI selection is performed manually, which introduces subjectivity, inconsistency and a lack of reproducibility. Previous studies have shown strong correlations between spatial molecular patterns and histological features, suggesting that readily available and cost-effective histology images can be leveraged to guide spatial omics experiments. Here we …

Utilizing Functional Neuroimaging To Study Early Language Development, Halie A Olson, Trevor K M Day, Kelly J Hiersche, Brittany L Manning, Holly Bradley, Soujin Choi, Gavkhar Abdurokhmonova, Sarah A Mccormick, Amy L Conrad, Dustin Scheinost, Kelly A Vaughn

Faculty, Staff and Student Publications

Language develops rapidly over the infant and toddler period and has been a key area of research within the field of developmental cognitive neuroscience. Understanding the neural basis of early language development may help us predict delays or disorders, recommend early interventions, and provide a deeper mechanistic understanding of how the brain supports language learning. While the ontogeny of many cognitive functions can be studied in animal models, language development can only be studied in human children. Thus, functional neuroimaging is critical for uncovering the neural basis of language in early development. The purpose of this review is to take …

Extracellular Domain Shedding Of Trop2 Activates Egfr Signaling To Drive Prostate Cancer Metastasis, Shiqin Liu, En-Chi Hsu, Merve Aslan, Fernando Garcia-Marques, Michelle Shen, Alifiani B Hartono, Francisco Solano, Kewei Le, Hyeonji Hwang, Chung S Lee, Abel Bermudez, Rosalie Nolley, Donna M Peehl, James D Brooks, Michael A Liss, Sharon J Pitteri, Tanya Stoyanova

Faculty, Staff and Student Publications

UNLABELLED: Metastasis is the main cause of prostate cancer-associated deaths, highlighting the urgent need to determine the mechanisms underlying prostate cancer progression. TROP2 (also known as tumor-associated calcium signal transducer 2) is an oncogenic transmembrane surface protein that is highly expressed in metastatic prostate cancer. Naturally occurring cleavage of TROP2 leads to a release of the TROP2 extracellular domain (TECD) into the extracellular environment. In this study, we identified an important functional role of TECD in prostate cancer metastasis. TECD was detectable in media from prostate cancer cells and serum from patients with clinically significant prostate cancer. Although shed TECD …

Differential Effects Of Murine Stroke Models On Dopaminergic Neurons, Glial Responses, And Neurobehavioral Outcomes, Sidra Tabassum, Heng Hu, Silin Wu, Shuning Huang, Bosco Seong Kyu Yang, Chang-Hun Lee, Aaron W Gusdon, Xuefang S Ren

Faculty, Staff and Student Publications

Stroke is a leading cause of disability worldwide, often resulting in persistent motor, cognitive, and emotional impairments. While the hippocampus and amygdala play critical roles in post-stroke behavioral changes, specific neuronal alterations and prolonged glial responses within these regions across different stroke types remain unclear. This study investigates the behavioral, neuronal, and glial effects of subarachnoid hemorrhage (SAH), transient middle cerebral artery occlusion (tMCAO), and photothrombotic stimulation (PTS) in mice. SAH and tMCAO models exhibited significant motor deficits, spatial and recognition memory impairments, and increased anxiety- and depressive-like behaviors, whereas the PTS model showed similar motor and cognitive impairments but …

Inhibiting Monocyte Migration Reduces Arterial Thrombosis And Facilitates Thrombolysis, Hee Jeong Jang, Jiwon Kim, Ha Kim, Taesu Kim, Jinyong Chung, Sebastian Cremer, Marvin Krohn-Grimberghe, Eo Jin Kim, Dawid Schellingerhout, Matthias Nahrendorf, Dong-Eog Kim

Faculty, Staff and Student Publications

Background: Monocytes contribute to the initiation and propagation of venous thrombosis. Little is known about the roles monocytes play in arterial thrombosis, the cause of stroke and myocardial infarction.

Methods: We investigated how CCR2 (CC chemokine receptor 2) knockout (-/-)-mediated monocyte deficiency affects platelet function, blood coagulation, thrombus volume, and thrombolytic susceptibility in 666 male mice with FeCl3-mediated carotid arterial thrombosis, including 365 C57BL/6 wild type (WT) mice, 295 CCR2-/- mice, and 6 CX3CR1-GFP (CX3C chemokine receptor 1-green fluorescent protein) mice.

Results: Intravital microscopy and flow cytometry showed that both neutrophils and monocytes were recruited to the acute arterial thrombus, …