Medical Specialties Commons^™

Time Dependent Analysis Of Rat Microglial Surface Markers In Traumatic Brain Injury Reveals Dynamics Of Distinct Cell Subpopulations, Assaf Gottlieb, Naama Toledano-Furman, Karthik S Prabhakara, Akshita Kumar, Henry W Caplan, Supinder Bedi, Charles S Cox, Scott D Olson

Faculty, Staff and Student Publications

Traumatic brain injury (TBI) results in a cascade of cellular responses, which produce neuroinflammation, partly due to the activation of microglia. Accurate identification of microglial populations is key to understanding therapeutic approaches that modify microglial responses to TBI and improve long-term outcome measures. Notably, previous studies often utilized an outdated convention to describe microglial phenotypes. We conducted a temporal analysis of the response to controlled cortical impact (CCI) in rat microglia between ipsilateral and contralateral hemispheres across seven time points, identified microglia through expression of activation markers including CD45, CD11b/c, and p2y12 receptor and evaluated their activation state using additional …

Healthcare Expenditure Associated With Polypharmacy In Older Adults With Cardiovascular Diseases, Min Ji Kwak, Mihyun Chang, Simbo Chiadika, David Aguilar, Elenir Avritscher, Ashish Deshmukh, Parag Goyal, Dae Hyun Kim, Rajender Aparasu, Holly M Holmes

Faculty, Staff and Student Publications

No abstract provided.

What Did We Learn About Vads In 2021?, Maya Guglin

The VAD Journal

This is our 8th annual literature review on mechanical circulatory support (MCS) devices.

Our previous reports were well received by the readers. The full text of the reviews for 2014, 2015, 2016, 2017, 2018, 2019, and 2020^1-7 were downloaded 821, 861, 701, 869, 951, 272, and 365 times, respectively.

In this review, we summarized the most interesting and important, from our standpoint, publications from 2021. There may be some slight overlap with the end of 2020 because some papers were published online first, and the year of the publication changed when they became …

Convection Enhanced Delivery Of The Oncolytic Adenovirus Delta24-Rgd In Patients With Recurrent Gbm: A Phase I Clinical Trial Including Correlative Studies, Erik H P Van Putten, Anne Kleijn, Victor W Van Beusechem, David Noske, Cor H J Lamers, Anna L De Goede, Sander Idema, Daphna Hoefnagel, Jenneke J Kloezeman, Juan Fueyo, Frederick F Lang, Charlotte E Teunissen, René M Vernhout, Cathy Bakker, Winald Gerritsen, David T Curiel, Arnold Vulto, Martine L M Lamfers, Clemens M F Dirven

Faculty, Staff and Student Publications

Purpose: Testing safety of Delta24-RGD (DNX-2401), an oncolytic adenovirus, locally delivered by convection enhanced delivery (CED) in tumor and surrounding brain of patients with recurrent glioblastoma.

Patients and methods: Dose-escalation phase I study with 3+3 cohorts, dosing 107 to 1 × 1011 viral particles (vp) in 20 patients. Besides clinical parameters, adverse events, and radiologic findings, blood, cerebrospinal fluid (CSF), brain interstitial fluid, and excreta were sampled over time and analyzed for presence of immune response, viral replication, distribution, and shedding.

Results: Of 20 enrolled patients, 19 received the oncolytic adenovirus Delta24-RGD, which was found to be safe and feasible. …

Cytospin-A Regulates Colorectal Cancer Cell Division And Migration By Modulating Stability Of Microtubules And Actin Filaments, Fan Fan, Jason Roszik, Ling Xia, Susmita Ghosh, Rui Wang, Xiangcang Ye, David Hawke, Lee M Ellis, Rajat Bhattacharya

Faculty, Staff and Student Publications

Simple Summary

In this study, we report the effects of depleting cytospin-A (CYTSA), also known as the sperm antigen with calponin homology and coiled-coil domain (SPECC1L) protein, on the proliferation and migration of colorectal cancer (CRC) cells. Mutations in this protein have been previously linked to different developmental disorders. In our studies, depletion of CYTSA in various CRC cells led to significant decreases in proliferation, increases in cell death, and increased formation of multinucleated cells. Knocking down CYTSA also led to severe inhibition of CRC cell migration and invasion. These effects could be related to a significant decrease in the …

A Photography-Based, Social Media Walking Intervention Targeting Autonomous Motivations For Physical Activity: Semistructured Interviews With Older Women, Michael C Robertson, Maria Chang Swartz, Ursela Christopherson, Jason R Bentley, Karen M Basen-Engquist, Debbe Thompson, Elena Volpi, Elizabeth J Lyons

Faculty, Staff and Students Publications

BACKGROUND: Older adult women are at risk for negative health outcomes that engaging in sustained physical activity can help prevent. However, promoting long-term maintenance of physical activity in this population has proven to be a challenge. Increasing autonomous motivations (ie, intrinsic, integrated, and identified regulations) for physical activity may facilitate enduring behavior change. Digitally delivered games for health that take a celebratory technology approach, that is, using technology to create new ways to experience valued behaviors and express valued beliefs, may be a useful way to target autonomous motivations for physical activity. Formative research with the target population is needed …

Targeting Non-Coding Rnas To Overcome Cancer Therapy Resistance, Baoqing Chen, Mihnea P Dragomir, Chen Yang, Qiaoqiao Li, David Horst, George A Calin

Faculty, Staff and Student Publications

It is now well known that non-coding RNAs (ncRNAs), rather than protein-coding transcripts, are the preponderant RNA transcripts. NcRNAs, particularly microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are widely appreciated as pervasive regulators of multiple cancer hallmarks such as proliferation, apoptosis, invasion, metastasis, and genomic instability. Despite recent discoveries in cancer therapy, resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy continue to be a major setback. Recent studies have shown that ncRNAs also play a major role in resistance to different cancer therapies by rewiring essential signaling pathways. In this review, we present the intricate mechanisms through …

Closing The Loop: Automatically Identifying Abnormal Imaging Results In Scanned Documents, Akshat Kumar, Heath Goodrum, Ashley Kim, Carly Stender, Kirk Roberts, Elmer V Bernstam

Faculty, Staff and Student Publications

OBJECTIVES: Scanned documents (SDs), while common in electronic health records and potentially rich in clinically relevant information, rarely fit well with clinician workflow. Here, we identify scanned imaging reports requiring follow-up with high recall and practically useful precision.

MATERIALS AND METHODS: We focused on identifying imaging findings for 3 common causes of malpractice claims: (1) potentially malignant breast (mammography) and (2) lung (chest computed tomography [CT]) lesions and (3) long-bone fracture (X-ray) reports. We train our ClinicalBERT-based pipeline on existing typed/dictated reports classified manually or using ICD-10 codes, evaluate using a test set of manually classified SDs, and compare against …

Neurofibromatosis Type 1 Has A Wide Spectrum Of Growth Hormone Excess, Fady Hannah-Shmouni, Giampaolo Trivellin, Pablo Beckers, Lefkothea P Karaviti, Maya Lodish, Christina Tatsi, Adekunle M Adesina, Fotini Adamidou, Gesthimani Mintziori, Jami L Josefson, Martha Quezado, Constantine A Stratakis

Faculty, Staff and Students Publications

Overgrowth due to growth hormone (GH) excess affects approximately 10% of patients with neurofibromatosis type 1 (NF1) and optic pathway glioma (OPG). Our aim is to describe the clinical, biochemical, pathological, and genetic features of GH excess in a retrospective case series of 10 children and adults with NF1 referred to a tertiary care clinical research center. Six children (median age = 4 years, range of 3−5 years), one 14-year-old adolescent, and three adults (median age = 42 years, range of 29−52 years) were diagnosed with NF1 and GH excess. GH excess was confirmed by the failure to suppress GH …

Autologous Stem Cell Transplantation For Large B-Cell Lymphoma With Secondary Central Nervous System Involvement, Serkan Akin, Chitra Hosing, Issa Khouri, Sairah Ahmed, Amin Alousi, Nathan Fowler, Jacinth Joseph, Jonathan Truxillo, Jeremy L Ramdial, Farzaneh Maadani, Gabriela Rondon, May Daher, Jin S Im, Raphael Steiner, Jason Westin, Swaminathan P Iyer, Bouthaina Dabaja, Paolo Anderlini, Uday R Popat, Muzaffar H Qazilbash, Christopher R Flowers, Elizabeth Shpall, Richard E Champlin, Yago Nieto, Samer A Srour

Faculty, Staff and Student Publications

Secondary central nervous system large B-cell lymphoma (SCNSL) is rare, with a generally poor prognosis. There is limited data about the role of autologous stem cell transplantation (ASCT) in these high-risk patients. We explored in this study treatment outcomes and prognostic factors for patients with SCNSL who underwent ASCT. We included all consecutive patients who underwent ASCT at our institution. Primary endpoints were progression-free survival (PFS) and overall survival (OS). One-hundred two patients were identified. Median age at transplant was 56 (range, 21-71) years. With a median follow-up of 56 (range, 1-256) months, the median PFS and OS were 40 …

Distinct Molecular And Immune Hallmarks Of Inflammatory Arthritis Induced By Immune Checkpoint Inhibitors For Cancer Therapy, Sang T Kim, Yanshuo Chu, Mercy Misoi, Maria E Suarez-Almazor, Jean H Tayar, Huifang Lu, Maryam Buni, Jordan Kramer, Emma Rodriguez, Zulekha Hussain, Sattva S Neelapu, Jennifer Wang, Amishi Y Shah, Nizar M Tannir, Matthew T Campbell, Don L Gibbons, Tina Cascone, Charles Lu, George R Blumenschein, Mehmet Altan, Bora Lim, Vincente Valero, Monica E Loghin, Janet Tu, Shannon N Westin, Aung Naing, Guillermo Garcia-Manero, Noha Abdel-Wahab, Hussein A Tawbi, Patrick Hwu, Isabella C Glitza Oliva, Michael A Davies, Sapna P Patel, Jun Zou, Andrew Futreal, Adi Diab, Linghua Wang, Roza Nurieva

Faculty, Staff and Student Publications

Immune checkpoint inhibitors are associated with immune-related adverse events (irAEs), including arthritis (arthritis-irAE). Management of arthritis-irAE is challenging because immunomodulatory therapy for arthritis should not impede antitumor immunity. Understanding of the mechanisms of arthritis-irAE is critical to overcome this challenge, but the pathophysiology remains unknown. Here, we comprehensively analyze peripheral blood and/or synovial fluid samples from 20 patients with arthritis-irAE, and unmask a prominent Th1-CD8

Variability Of Care And Access To Transplantation For Children With Biliary Atresia Who Need A Liver Replacement, Jean De Ville De Goyet, Toni Illhardt, Christophe Chardot, Peace N Dike, Ulrich Baumann, Katherine Brandt, Barbara E Wildhaber, Mikko Pakarinen, Fabrizio Di Francesco, Ekkehard Sturm, Marianna Cornet, Caroline Lemoine, Eva Doreen Pfister, Ana M Calinescu, Maria Hukkinen, Sanjiv Harpavat, Fabio Tuzzolino, Riccardo Superina

Faculty, Staff and Students Publications

Background & Aims: Biliary atresia (BA) is the commonest single etiology indication for liver replacement in children. As timely access to liver transplantation (LT) remains challenging for small BA children (with prolonged waiting time being associated with clinical deterioration leading to both preventable pre- and post-transplant morbidity and mortality), the care pathway of BA children in need of LT was analyzed—from diagnosis to LT—with particular attention to referral patterns, timing of referral, waiting list dynamics and need for medical assistance before LT. Methods: International multicentric retrospective study. Intent-to-transplant study analyzing BA children who had indication for LT early in life …

Human Pancreatic Microenvironment Promotes Β-Cell Differentiation Via Non-Canonical Wnt5a/Jnk And Bmp Signaling, Jolanta Chmielowiec, Wojciech J Szlachcic, Diane Yang, Marissa A Scavuzzo, Katrina Wamble, Alejandro Sarrion-Perdigones, Omaima M Sabek, Koen J T Venken, Malgorzata Borowiak

Faculty, Staff and Students Publications

In vitro derivation of pancreatic β-cells from human pluripotent stem cells holds promise as diabetes treatment. Despite recent progress, efforts to generate physiologically competent β-cells are still hindered by incomplete understanding of the microenvironment's role in β-cell development and maturation. Here, we analyze the human mesenchymal and endothelial primary cells from weeks 9-20 fetal pancreas and identify a time point-specific microenvironment that permits β-cell differentiation. Further, we uncover unique factors that guide in vitro development of endocrine progenitors, with WNT5A markedly improving human β-cell differentiation. WNT5A initially acts through the non-canonical (JNK/c-JUN) WNT signaling and cooperates with Gremlin1 to inhibit …

Predicting The Need For Therapeutic Intervention And Mortality In Acute Pancreatitis: A Two-Center International Study Using Machine Learning, Na Shi, Lan Lan, Jiawei Luo, Ping Zhu, Thomas R W Ward, Peter Szatmary, Robert Sutton, Wei Huang, John A Windsor, Xiaobo Zhou, Qing Xia

Faculty, Staff and Student Publications

BACKGROUND: Current approaches to predicting intervention needs and mortality have reached 65-85% accuracy, which falls below clinical decision-making requirements in patients with acute pancreatitis (AP). We aimed to accurately predict therapeutic intervention needs and mortality on admission, in AP patients, using machine learning (ML).

METHODS: Data were obtained from three databases of patients admitted with AP: one retrospective (Chengdu) and two prospective (Liverpool and Chengdu) databases. Intervention and mortality differences, as well as potential predictors, were investigated. Univariate analysis was conducted, followed by a random forest ML algorithm used in multivariate analysis, to identify predictors. The ML performance matrix was …

Ndrg1 In Aggressive Breast Cancer Progression And Brain Metastasis, Emilly S Villodre, Xiaoding Hu, Bedrich L Eckhardt, Richard Larson, Lei Huo, Ester C Yoon, Yun Gong, Juhee Song, Shuying Liu, Naoto T Ueno, Savitri Krishnamurthy, Stefan Pusch, Debu Tripathy, Wendy A Woodward, Bisrat G Debeb

Faculty, Staff and Student Publications

BACKGROUND: N-Myc downstream regulated gene 1 (NDRG1) suppresses metastasis in many human malignancies, including breast cancer, yet has been associated with worse survival in patients with inflammatory breast cancer. The role of NDRG1 in the pathobiology of aggressive breast cancers remains elusive.

METHODS: To study the role of NDRG1 in tumor growth and brain metastasis in vivo, we transplanted cells into cleared mammary fat pads or injected them in tail veins of SCID/Beige mice (n = 7-10 per group). NDRG1 protein expression in patient breast tumors (n = 216) was assessed by immunohistochemical staining. Kaplan-Meier method with 2-sided log-rank test …

Bismuth Nanoparticle And Polyhydroxybutyrate Coatings Enhance The Radiopacity Of Absorbable Inferior Vena Cava Filters For Fluoroscopy-Guided Placement And Longitudinal Computed Tomography Monitoring In Pigs, Jossana A Damasco, Steven Y Huang, Joy Vanessa D Perez, John Andrew T Manongdo, Katherine A Dixon, Malea L Williams, Megan C Jacobsen, Roland Barbosa, Gino Martin Canlas, Gouthami Chintalapani, Adam D Melancon, Rick R Layman, Natalie W Fowlkes, Elizabeth M Whitley, Marites P Melancon

Faculty, Staff and Student Publications

Inferior vena cava filters (IVCFs) constructed with poly-

An Imaging Biomarker Of Tumor-Infiltrating Lymphocytes To Risk-Stratify Patients With Hpv-Associated Oropharyngeal Cancer, Germán Corredor, Paula Toro, Can Koyuncu, Cheng Lu, Christina Buzzy, Kaustav Bera, Pingfu Fu, Mitra Mehrad, Kim A Ely, Mojgan Mokhtari, Kailin Yang, Deborah Chute, David J Adelstein, Lester D R Thompson, Justin A Bishop, Farhoud Faraji, Wade Thorstad, Patricia Castro, Vlad Sandulache, Shlomo A Koyfman, James S Lewis, Anant Madabhushi

Faculty, Staff and Students Publications

BACKGROUND: Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) has excellent control rates compared to nonvirally associated OPSCC. Multiple trials are actively testing whether de-escalation of treatment intensity for these patients can maintain oncologic equipoise while reducing treatment-related toxicity. We have developed OP-TIL, a biomarker that characterizes the spatial interplay between tumor-infiltrating lymphocytes (TILs) and surrounding cells in histology images. Herein, we sought to test whether OP-TIL can segregate stage I HPV-associated OPSCC patients into low-risk and high-risk groups and aid in patient selection for de-escalation clinical trials.

METHODS: Association between OP-TIL and patient outcome was explored on whole slide …

Racial Disparities In Prostate Cancer: A Complex Interplay Between Socioeconomic Inequities And Genomics, Dallin Lowder, Kinza Rizwan, Collin Mccoll, Alyssa Paparella, Michael Ittmann, Nicholas Mitsiades, Salma Kaochar

Faculty, Staff and Students Publications

The largest US cancer health disparity exists in prostate cancer, with Black men having more than a two-fold increased risk of dying from prostate cancer compared to all other races. This disparity is a result of a complex network of factors including socioeconomic status (SES), environmental exposures, and genetics/biology. Inequity in the US healthcare system has emerged as a major driver of disparity in prostate cancer outcomes and has raised concerns that the actual incidence rates may be higher than current estimates. However, emerging studies argue that equalizing healthcare access will not fully eliminate racial health disparities and highlight the …

Envisioning Future Urinary Tract Infection Diagnostics, Robin Patel, Christopher R Polage, Jennifer Dien Bard, Larissa May, Francesca M Lee, Valeria Fabre, Mary K Hayden, Sarah D B Doernberg, David A Haake, Barbara W Trautner, Larissa Grigoryan, Ephraim L Tsalik, Kimberly E Hanson

Faculty, Staff and Students Publications

Urinary tract infections (UTIs) are among the most common bacterial infections in the United States and are a major driver of antibiotic use, both appropriate and inappropriate, across healthcare settings. Novel UTI diagnostics are a strategy that might enable better UTI treatment. Members of the Antibacterial Resistance Leadership Group Laboratory Center and the Infectious Diseases Society of America Diagnostics Committee convened to envision ideal future UTI diagnostics, with a view towards improving delivery of healthcare, patient outcomes and experiences, and antibiotic use, addressing which types of UTI diagnostics are needed and how companies might approach development of novel UTI diagnostics.

Exploiting 4–1bb Immune Checkpoint To Enhance The Efficacy Of Oncolytic Virotherapy For Diffuse Intrinsic Pontine Gliomas, Virginia Laspidea, Montserrat Puigdelloses, Sara Labiano, Lucía Marrodán, Marc Garcia-Moure, Marta Zalacain, Marisol Gonzalez-Huarriz, Naiara Martínez-Vélez, Iker Ausejo-Mauleon, Daniel De La Nava, Guillermo Herrador-Cañete, Javier Marco-Sanz, Elisabeth Guruceaga, Carlos E De Andrea, María Villalba, Oren Becher, Massimo Squatrito, Verónica Matía, Jaime Gállego Pérez-Larraya, Ana Patiño-García, Sumit Gupta, Candelaria Gomez-Manzano, Juan Fueyo, Marta M Alonso

Faculty, Staff and Student Publications

Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors, and patient survival has not changed despite many therapeutic efforts, emphasizing the urgent need for effective treatments. Here, we evaluated the anti-DIPG effect of the oncolytic adenovirus Delta-24-ACT, which was engineered to express the costimulatory ligand 4-1BBL to potentiate the antitumor immune response of the virus. Delta-24-ACT induced the expression of functional 4-1BBL on the membranes of infected DIPG cells, which enhanced the costimulation of CD8+ T lymphocytes. In vivo, Delta-24-ACT treatment of murine DIPG orthotopic tumors significantly improved the survival of treated mice, leading to long-term survivors that developed …

Lymphocyte Depletion Rate As A Biomarker Of Radiation Dose To Circulating Lymphocytes During Fractionated Partial-Body Radiation Therapy, Susannah G Ellsworth, Anirudh Yalamanchali, Tim Lautenschlaeger, Stuart A Grossman, Clemens Grassberger, Steven H Lin, Radhe Mohan

Faculty, Staff and Student Publications

Purpose: Radiation causes exponential depletion of circulating lymphocyte populations; in turn, radiation-induced lymphopenia is associated with worse survival for many solid tumors, possibly owing to attenuated antitumor immune responses. Identifying reliable and reproducible methods of calculating the radiation dose to circulating immune cells may facilitate development of techniques to reduce the risk and severity of radiation-induced toxic effects to circulating lymphocytes.

Methods and materials: Patient-specific lymphocyte loss rates were derived from a clinical data set including 684 adult patients with solid tumors. Multivariable linear regression was used to model the relationship between the lymphocyte loss rate and physical parameters of …

Retention Of Physician Assistants Within A Specialty After Completion Of A Postgraduate Training Program, John Ansiaux Pa-C, Carly Farrell Pa-C, Kathryn Hess Pa-C, Aubrey White Pa-C, Charlotte Peeters Pa-C, Jill Schulten Pa-C, Ryan Krasnosky Mpas, Pa-C, Dfaapa, Drph

Journal of Nursing & Interprofessional Leadership in Quality & Safety

Background: The advantages of a specialized training program have led to over 84 postgraduate training programs for Physician Assistants (PAs) covering over 25 specialties. Employee lateral mobility is more prevalent within the PA profession, which allows PA providers to switch between medical specialties. The versatility of PAs promotes higher turnover rates compared to physician counterparts. These high turnover rates can result in increased institutional burden. Postgraduate PA programs provide pre-employment exposure to more in-depth medical training, enabling a well-rounded knowledge base of the PA’s roles and responsibilities, minimizing turnover rates.

Purpose: The goal of this survey study is to identify …

The Impact Of Pediatric Opioid-Related Visits On Us Emergency Departments, Tiffany Champagne-Langabeer, Marylou Cardenas-Turanzas, Irma T Ugalde, Christine Bakos-Block, Angela L Stotts, Lisa Cleveland, Steven Shoptaw, James R Langabeer

Faculty, Staff and Student Publications

BACKGROUND: While there is significant research exploring adults' use of opioids, there has been minimal focus on the opioid impact within emergency departments for the pediatric population.

METHODS: We examined data from the Agency for Healthcare Research, the National Emergency Department Sample (NEDS), and death data from the Centers for Disease Control and Prevention. Sociodemographic and financial variables were analyzed for encounters during 2014-2017 for patients under age 18, matching diagnoses codes for opioid-related overdose or opioid use disorder.

RESULTS: During this period, 59,658 children presented to an ED for any diagnoses involving opioids. The majority (68.5%) of visits were …

Repurposing Probenecid For The Treatment Of Heart Failure (Re-Prosper-Hf): A Study Protocol For A Randomized Placebo-Controlled Clinical Trial, Jack Rubinstein, Nathan Robbins, Karen Evans, Gabrielle Foster, Kevin Mcconeghy, Toluwalope Onadeko, Julie Bunke, Melanie Parent, Xi Luo, Jacob Joseph, Wen-Chih Wu

Faculty, Staff and Student Publications

BACKGROUND: Improving contractility in heart failure with reduced ejection fraction (HFrEF) has resurfaced as a potential treatment goal. Inotropic therapy is now better understood through its underlying mechanism as opposed to the observed effect of increasing contractility. Calcitropes are a subgroup of inotropes that largely depend on the stimulation of adenylyl cyclase to transform ATP into cyclic adenosine monophosphate (cAMP). At least two clinically relevant calcitropes-istaroxime and probenecid-improve contractility through an increase in systolic intracellular calcium without activating cAMP production. Probenecid, which has been safely used clinically for decades in non-cardiac conditions, has recently been identified as an agonist of …

Loss-Of-Function Variants In Tiam1 Are Associated With Developmental Delay, Intellectual Disability, And Seizures, Shenzhao Lu, Rebecca Hernan, Paul C Marcogliese, Yan Huang, Tracy S Gertler, Meltem Akcaboy, Shiyong Liu, Hyung-Lok Chung, Xueyang Pan, Xiaoqin Sun, Melahat Melek Oguz, Ulkühan Oztoprak, Jeroen H F De Baaij, Jelena Ivanisevic, Erin Mcginnis, Maria J Guillen Sacoto, Wendy K Chung, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

TIAM Rac1-associated GEF 1 (TIAM1) regulates RAC1 signaling pathways that affect the control of neuronal morphogenesis and neurite outgrowth by modulating the actin cytoskeletal network. To date, TIAM1 has not been associated with a Mendelian disorder. Here, we describe five individuals with bi-allelic TIAM1 missense variants who have developmental delay, intellectual disability, speech delay, and seizures. Bioinformatic analyses demonstrate that these variants are rare and likely pathogenic. We found that the Drosophila ortholog of TIAM1, still life (sif), is expressed in larval and adult central nervous system (CNS) and is mainly expressed in a subset of neurons, but not in …

Hsp90-Cdc37 Functions As A Chaperone For The Oncogenic Fgfr3-Tacc3 Fusion, Tao Li, Farideh Mehraein-Ghomi, M Elizabeth Forbes, Sanjeev V Namjoshi, E Ashley Ballard, Qianqian Song, Ping-Chieh Chou, Xuya Wang, Brittany C Parker Kerrigan, Frederick F Lang, Glenn Lesser, Waldemar Debinski, Xuejun Yang, Wei Zhang

Faculty, Staff and Student Publications

The FGFR3-TACC3 (F3-T3) fusion gene was discovered as an oncogenic molecule in glioblastoma and bladder cancers, and has subsequently been found in many cancer types. Notably, F3-T3 was found to be highly expressed in both untreated and matched recurrence glioblastoma under the concurrent radiotherapy and temozolomide (TMZ) treatment, suggesting that targeting F3-T3 is a valid strategy for treatment. Here, we show that the F3-T3 protein is a client of heat shock protein 90 (HSP90), forming a ternary complex with the cell division cycle 37 (CDC37). Deprivation of HSP90 or CDC37 disrupts the formation of the ternary complex, which destabilizes glycosylated …

Gestational Age Variation In Human Placental Drug Transporters, Laura Goetzl, Nune Darbinian, Nana Merabova, Lindsay C Devane, Sammanda Ramamoorthy

Faculty, Staff and Student Publications

Patient and providers' fear of fetal exposure to medications may lead to discontinuation of treatment, disease relapse, and maternal morbidity. Placental drug transporters play a critical role in fetal exposure through active transport but the majority of data are limited to the 3rd trimester, when the majority of organogenesis has already occurred. Our objective was to define gestational age (GA) dependent changes in protein activity, expression and modifications of five major placental drug transporters: SERT, P-gp, NET, BCRP and MRP3. Apical brush border membrane fractions were prepared from fresh 1st, 2nd and 3rd trimester human placentas collected following elective pregnancy …

Targeting The Nrf2/Ho-1 Antioxidant Pathway In Flt3-Itd-Positive Aml Enhances Therapy Efficacy, Sankaranarayan Kannan, Mary E Irwin, Shelley M Herbrich, Tiewei Cheng, Lanisha L Patterson, Marisa J L Aitken, Kapil Bhalla, M James You, Marina Konopleva, Patrick A Zweidler-Mckay, Joya Chandra

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) is a molecularly heterogenous hematological malignancy, with one of the most common mutations being internal tandem duplication (ITD) of the juxtamembrane domain of the fms-like tyrosine kinase receptor-3 (FLT3). Despite the development of FLT3-directed tyrosine kinase inhibitors (TKI), relapse and resistance are problematic, requiring improved strategies. In both patient samples and cell lines, FLT3-ITD raises levels of reactive oxygen species (ROS) and elicits an antioxidant response which is linked to chemoresistance broadly in AML. NF-E2-related factor 2 (NRF2) is a transcription factor regulating the antioxidant response including heme oxygenase -1 (HO-1), a heat shock protein implicated …

Demographic And Regional Trends Of Mortality In Patients With Aortic Dissection In The United States, 1999 To 2019, Salik Nazir, Robert W Ariss, Abdul Mannan Khan Minhas, Rochell Issa, Erin D Michos, Yochai Birnbaum, George V Moukarbel, P Kasi Ramanathan, Hani Jneid

Faculty, Staff and Students Publications

Background Aortic dissection (AoD) is associated with high morbidity and mortality. However, the burden of AoD mortality is not well characterized, and contemporary data and mortality trends in different demographic and geographic subgroups have not been described. Methods and Results Trends in AoD mortality were assessed using a cross-sectional analysis of the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database. Crude and age-adjusted mortality rates (AAMR) per 1 million people with associated annual percent changes were determined. Joinpoint regression was used to assess trends in the overall sample and different demographic (sex, race and ethnicity, …

Perceptions Of Weight Status And Energy Balance Behaviors Among Patients With Non-Alcoholic Fatty Liver Disease, Natalia I Heredia, Ruchi Gaba, Yan Liu, Shilpa Jain, Manasi Rungta, Manav Rungta, Hashem B El-Serag, Fasiha Kanwal, Aaron P Thrift, Maya Balakrishnan

Faculty, Staff and Students Publications

Weight loss through behavioral modification is central to treating non-alcoholic fatty liver disease (NAFLD). To achieve this, patients need to accurately self-perceive their health behaviors. We aimed to identify predictors of concordance between self-perception and objective measures of body weight, physical activity (PA) and dietary behaviors. We used data from the Harris County NAFLD Cohort, an ongoing prospective study in a regional safety-net healthcare system. Patients completed self-administered baseline questionnaires on demographics, diet, PA, and self-perceptions. We assessed concordance between actual and self-perceived body weight and energy-balance behaviors. Multivariable logistic regression identified predictors of concordance. Patients (n = 458; average …