Digital Commons Network^™

Evidence Of Neurovascular Water Exchange And Endothelial Vascular Dysfunction In Schizophrenia: An Exploratory Study, Xingfeng Shao, Wyatt Marshall, Alexa Yuen, Mark Kvarta, Yizhou Ma, Xiaoming Du, Si Gao, Osamah Saeedi, Heather Bruce, Patrick Donnelly, Hugh O'Neill, Alan R Shuldiner, Braxton D Mitchell, Peter Kochunov, L Elliot Hong

Faculty, Staff and Student Publications

BACKGROUND AND HYPOTHESIS: Mounting evidence supports cerebrovascular contributions to schizophrenia spectrum disorder (SSD) but with unknown mechanisms. The blood-brain barrier (BBB) is at the nexus of neural-vascular exchanges, tasked with regulating cerebral homeostasis. BBB abnormalities in SSD, if any, are likely more subtle compared to typical neurological insults and imaging measures that assess large molecule BBB leakage in major neurological events may not be sensitive enough to directly examine BBB abnormalities in SSD.

STUDY DESIGN: We tested the hypothesis that neurovascular water exchange (Kw) measured by non-invasive diffusion-prepared arterial spin label MRI (n = 27 healthy controls [HC], n = …

Heart Failure Burden In Oman As A Mid-East Exemplar Versus Global Perspectives: An Integrative Review, Maryam Alharrasi, Chandrani Isac, Joy Kabasindi Kamanyire

Journal of the Saudi Heart Association

Heart failure (HF), a clinical syndrome caused by a structural and functional cardiac abnormality and corroborated by elevated natriuretic peptide levels and pulmonary congestion. This study intends to investigate the state of heart failure (HF) in Oman and assess it in comparison of global trends. Ten published literatures from the past 20 years were included after a thorough search of databases (Arab World Research Source, EBSCOhost, Medline, and Google Scholar). These studies were reviewed considering the global literature. We have observed an increase in HF cases especially in older adults, over the past two decades in Oman. Acute coronary syndrome …

Stem-Like Cd4+T Cells In Perivascular Tertiary Lymphoid Structures Sustain Autoimmune Vasculitis, Yuki Sato, Abhinav Jain, Shozo Ohtsuki, Hirohisa Okuyama, Ines Sturmlechner, Kevin-Phu C Le, Gerald J Berry, Kenneth J Warrington, Jörg J Goronzy, Cornelia M Weyand

Faculty, Staff and Student Publications

Autoimmune vasculitis of the medium and large elastic arteries can cause blindness, stroke, aortic arch syndrome, and aortic aneurysm. The disease is often refractory to immunosuppressive therapy and progresses over decades as smoldering aortitis. How the granulomatous infiltrates in the vessel wall are maintained and how tissue-infiltrating T cells and macrophages are replenished are unknown. Single-cell and whole-tissue transcriptomic studies of immune cell populations in vasculitic arteries identified a CD4+ T cell population with stem cell-like features. CD4+ T cells supplying the tissue-infiltrating and tissue-damaging effector T cells survived in tertiary lymphoid structures around adventitial vasa vasora, expressed the transcription …

Strategies For Maintaining Brain Health: The Role Of Stroke Risk Factors Unique To Elderly Women, Melanie R Moody

Faculty, Staff and Student Publications

We have conducted a stability study of a complex liposomal pharmaceutical product, Atheroglitatide (AGT), stored at three temperatures, 4, 24, and 37 °C, for up to six months. The six parameters measured were functions of liposomal integrity (size and number), drug payload (loading efficiency), targeting peptide integrity (conjugation efficiency and specific avidity), and echogenicity (ultrasound-dependent controlled drug release), which were considered most relevant to the product's intended use. At 4 °C, liposome diameter trended upward, indicative of aggregation, while liposome number per mg lipid and echogenicity trended downward. At 24 °C, peptide conjugation efficiency (CE) and targeting efficiency (TE, specific …

A Pre-Medical Student’S Reconciliation Of Feminist Narratives Regarding Women’S Health: A Consideration Of Perspectives On Childbirth In The U.S., Laura Clayton

sprinkle: an undergraduate journal of feminist and queer studies

Many feminists argue that one major negative aspect of reproductive healthcare in the U.S. is the common over-medicalization of women during childbirth, including potentially unnecessary procedures such as cesarean-section and episiotomy. As a solution, they advocate for increased involvement of midwives in childbirth practices, as midwives allow women to give birth at home with minimal medical intervention. This paper analyzes the benefits of midwifery as well as the current increased risk associated with homebirth in the U.S. Additionally, it questions the damaging stigma associated with assumptions of cesarean-section as a suboptimal outcome. A false dichotomy has developed in our culture …

The Impact Of Covid-19 On Carotid-Femoral Pulse Wave Velocity: A Systematic Review And Meta-Analysis, Tomasz Targowski, Robert Olszewski, Stepan Feduniw, Karolina Petryka, Lukasz Szarpak

Faculty, Staff and Students Publications

COVID-19 is a complex multisystemic disease that can result in long-term complications and, in severe cases, death. This study investigated the effect of COVID-19 on carotid–femoral pulse wave velocity (cfPWV) as a measurement to evaluate its impact on arterial stiffness and might help predict COVID-19-related cardiovascular (CV) complications. PubMed, Web of Science, Embase, and the Cochrane Library were searched for relevant studies, and meta-analysis was performed. The study protocol was registered in PROSPERO (nr. CRD42023434326). The Newcastle–Ottawa Quality Scale was used to evaluate the quality of the included studies. Nine studies reported cfPWV among COVID-19 patients and control groups. The …

Low-Grade Serous Ovarian Cancer: Expert Consensus Report On The State Of The Science, Rachel N Grisham, Brian M Slomovitz, Nicole Andrews, Susana Banerjee, Jubilee Brown, Herman Chui, Amanda N Fader, Stephanie Gaillard, Charlie Gourley, Anil K Sood, Bradley J Monk, Kathleen N Moore, Isabelle Ray-Coquard, Ie-Ming Shih, Shannon N Westin, Kwong-Kwok Wong, David M Gershenson

Faculty, Staff and Student Publications

Compared with high-grade serous carcinoma, low-grade serous carcinoma of the ovary or peritoneum is a less frequent epithelial ovarian cancer type that is poorly sensitive to chemotherapy and affects younger women, many of whom endure years of ineffective treatments and poor quality of life. The pathogenesis of this disease and its management remain incompletely understood. However, recent advances in the molecular characterization of the disease and identification of novel targeted therapies with activity in low-grade serous carcinoma offer the promise of improved outcomes. To update clinicians regarding recent scientific and clinical trial advancements and discuss unanswered questions related to low-grade …

Taz2 Truncation Confers Overactivation Of P300 And Cellular Vulnerability To Hdac Inhibition, Longxia Xu, Hongwen Xuan, Wei He, Liang Zhang, Mengying Huang, Hong Wen, Xiaobing Shi

Faculty, Staff and Student Publications

The histone acetyltransferase p300/CBP is composed of several conserved domains, among which, the TAZ2 domain is known as a protein-protein interaction domain that binds to E1A and various transcription factors. Here we show that TAZ2 has a HAT autoinhibitory function. Truncating p300/CBP at TAZ2 leads to hyperactive HAT and elevated histone H3K27 and H3K18 acetylation in cells. Mechanistically, TAZ2 cooperates with other HAT neighboring domains to maintain the HAT active site in a 'closed' state. Truncating TAZ2 or binding of transcription factors to TAZ2 induces a conformational change that 'opens' the active site for substrate acetylation. Importantly, genetic mutations that …

Kneiffiella Palmae: A Non-Aspergillus Fungal Infection Isolated From A Pulmonary Nodule In A Child With Chronic Granulomatous Disease, Bianca E. Ituarte, Connie Canete-Gibas, Nathan P. Wiederhold, Liset Olarte

Manuscripts, Articles, Book Chapters and Other Papers

We report the first known human case of Kneiffiella palmae in the medical literature. K. palmae was isolated from a pulmonary nodule in a 7-year-old male with chronic granulomatous disease. The mold was identified as K. palmae at a national reference laboratory, where 17 other human respiratory samples tested positive for K. palmae from 2013 to 2021. Optimal antimicrobial treatment is unknown, but azoles and amphotericin B demonstrated in vitro activity against each tested isolate.

Hla-Ii Alleles Influence Physical And Behavioral Responses To A Whey Allergen In A Transgenic Mouse Model Of Cow's Milk Allergy, Danielle L. Germundson, Suba Nookala, Nicholas A. Smith, Yassmine Warda, Kumi Nagamoto-Combs

Biomedical Sciences Faculty Publications

The symptoms of food allergies vary significantly between individuals, likely due to genetic determinants. In humans, allergy development is initiated by antigen-presenting cells via class II human leukocyte antigen (HLA-II). The HLA-II gene is highly polymorphic, and its allelic variance is thought to influence the susceptibility of individuals to a particular allergen. However, whether antigen presentation by different HLA-II variants contributes to symptom variation is not clear. We hypothesized that HLA-II allelic variance affects symptom phenotypes, including immediate physical reactions and delayed behavioral changes, in individuals with food hypersensitivity. To test our hypothesis, male and female mice of three transgenic …

Sex-Dependent Effects Of Intestinal Microbiome Manipulation In A Mouse Model Of Alzheimer’S Disease, Harpreet Kaur, Suba Nookala, Surjeet Singh, Santhosh Mukundan, Kumi Nagamoto-Combs, Colin K. Combs

Biomedical Sciences Faculty Publications

Mechanisms linking intestinal bacteria and neurodegenerative diseases such as Alzheimer’s disease (AD) are still unclear. We hypothesized that intestinal dysbiosis might potentiate AD, and manipulating the microbiome to promote intestinal eubiosis and immune homeostasis may improve AD-related brain changes. This study assessed sex differences in the effects of oral probiotic, antibiotics, and synbiotic treatments in the AppNL-G-F mouse model of AD. The fecal microbiome demonstrated significant correlations between bacterial genera in AppNL-G-F mice and Aβ plaque load, gliosis, and memory performance. Female and not male AppNL-G-F mice fed probiotic but not synbiotic exhibited a decrease in Aβ plaques, microgliosis, brain …

Bacteroides Fragilis In The Gut Microbiomes Of Alzheimer’S Disease Activates Microglia And Triggers Pathogenesis In Neuronal C/Ebpβ Transgenic Mice, Yiyuan Xia, Yifan Xiao, Zi-Hao Wang, Ashfaqul M. Alam, John P. Haran, Beth A. Mccormick, Xiji Shu, Xiaochuan Wang, Keqiang Ye

Markey Cancer Center Faculty Publications

Gut dysbiosis contributes to Alzheimer’s disease (AD) pathogenesis, and Bacteroides strains are selectively elevated in AD gut microbiota. However, it remains unknown which Bacteroides species and how their metabolites trigger AD pathologies. Here we show that Bacteroides fragilis and their metabolites 12-hydroxy-heptadecatrienoic acid (12-HHTrE) and Prostaglandin E2 (PGE2) activate microglia and induce AD pathogenesis in neuronal C/EBPβ transgenic mice. Recolonization of antibiotics cocktail-pretreated Thy1-C/EBPβ transgenic mice with AD patient fecal samples elicits AD pathologies, associated with C/EBPβ/Asparaginyl endopeptidase (AEP) pathway upregulation, microglia activation, and cognitive disorders compared to mice receiving healthy donors’ fecal microbiota transplantation (FMT). Microbial 16S rRNA sequencing …

A Novel Grk3-Hdac2 Regulatory Pathway Is A Key Direct Link Between Neuroendocrine Differentiation And Angiogenesis In Prostate Cancer Progression, Dayong Zheng, Mohit Hulsurkar, Michael Bakhoum, Ning Su, Han Yang, Tao Shen, Wenliang Li

Faculty, Staff and Students Publications

The mechanisms underlying the progression of prostate cancer (PCa) to neuroendocrine prostate cancer (NEPC), an aggressive PCa variant, are largely unclear. Two prominent NEPC phenotypes are elevated NE marker expression and heightened angiogenesis. Identifying the still elusive direct molecular links connecting angiogenesis and neuroendocrine differentiation (NED) is crucial for our understanding and targeting of NEPC. Here we found that histone deacetylase 2 (HDAC2), whose role in NEPC has not been reported, is one of the most upregulated epigenetic regulators in NEPC. HDAC2 promotes both NED and angiogenesis. G protein-coupled receptor kinase 3 (GRK3), also upregulated in NEPC, is a critical …

Myths And Methodologies: Cardiopulmonary Exercise Testing For Surgical Risk Stratification In Patients With An Abdominal Aortic Aneurysm; Balancing Risk Over Benefit, Michael H Lewis, Ahmed Abd Aldayem, Chistopher P Twine, Wael Awad, Matti Jubouri, Idhrees Mohammed, Carlos A Mestres, Edward P Chen, Joseph S Coselli, Ian M Williams, Mohamad Bashir, International Academic Surgical Consortium (Thalamus)

Faculty, Staff and Students Publications

The extent to which patients with an abdominal aortic aneurysm (AAA) should exercise remains unclear, given theoretical concerns over the perceived risk of blood pressure-induced rupture, which is often catastrophic. This is especially pertinent during cardiopulmonary exercise testing, when patients are required to perform incremental exercise to symptom-limited exhaustion for the determination of cardiorespiratory fitness. This multimodal metric is being used increasingly as a complementary diagnostic tool to inform risk stratification and subsequent management of patients undergoing AAA surgery. In this review, we bring together a multidisciplinary group of physiologists, exercise scientists, anaesthetists, radiologists and surgeons to challenge the enduring …

The Reviewer Academy Of The Society Of Critical Care Medicine: Key Principles And Strategic Plan, Jan Hau Lee, Heather Meissen, Brenda M Morrow, Lama Nazer, Richard D Branson, Kirby P Mayer, Natalie Napolitano, Meghan B Lane-Fall, Andrea Sikora, Preeti R John, R Phillip Dellinger, Margaret Parker, Andrew Argent, Adjoa Boateng, Thomas P Green, Sapna R Kudchadkar, David M Maslove, Megan A Rech, Lauren R Sorce, Robert C Tasker, Timothy G Buchman, Paul A Checchia

Faculty, Staff and Students Publications

The Society of Critical Care Medicine (SCCM) Reviewer Academy seeks to train and establish a community of trusted, reliable, and skilled peer reviewers with diverse backgrounds and interests to promote high-quality reviews for each of the SCCM journals. Goals of the Academy include building accessible resources to highlight qualities of excellent manuscript reviews; educating and mentoring a diverse group of healthcare professionals; and establishing and upholding standards for insightful and informative reviews. This manuscript will map the mission of the Reviewer Academy with a succinct summary of the importance of peer review, process of reviewing a manuscript, and the expected …

A Defect In Mitochondrial Fatty Acid Synthesis Impairs Iron Metabolism And Causes Elevated Ceramide Levels, Paul C Marcogliese, Zhongyuan Zuo, Rishi V Shridharan, Jun Hyoung Park, Undiagnosed Diseases Networ, Guang Lin, Ming Ge, Gali Heimer, Jennefer N Kohler, Matthew T Wheeler, Benny A Kaipparettu, Akhilesh Pandey, Hugo J Bellen

Faculty, Staff and Students Publications

In most eukaryotic cells, fatty acid synthesis (FAS) occurs in the cytoplasm and in mitochondria. However, the relative contribution of mitochondrial FAS (mtFAS) to the cellular lipidome is not well defined. Here we show that loss of function of Drosophila mitochondrial enoyl coenzyme A reductase (Mecr), which is the enzyme required for the last step of mtFAS, causes lethality, while neuronal loss of Mecr leads to progressive neurodegeneration. We observe a defect in Fe-S cluster biogenesis and increased iron levels in flies lacking mecr, leading to elevated ceramide levels. Reducing the levels of either iron or ceramide suppresses the neurodegenerative …

Characterization And Quantification Of Adeno-Associated Virus Capsid-Loading States By Multi-Wavelength Analytical Ultracentrifugation With Ultrascan, Zhe Qu, Lauren Tomlinson, John Forsey, Viviana Gradinaru, Kazuhiro Oka, Borries Demeler

Faculty, Staff and Students Publications

Aim:

We present multi-wavelength (MW) analytical ultracentrifugation (AUC) methods offering superior accuracy for adeno-associated virus characterization and quantification.

Methods:

Experimental design guidelines are presented for MW sedimentation velocity and analytical buoyant density equilibrium AUC.

Results:

Our results were compared with dual-wavelength AUC, transmission electron microscopy and mass photometry. In contrast to dual-wavelength AUC, MW-AUC correctly quantifies adeno-associated virus capsid ratios and identifies contaminants. In contrast to transmission electron microscopy, partially filled capsids can also be detected and quantified. In contrast to mass photometry, first-principle results are obtained.

Conclusion:

Our study demonstrates the improved information provided by MW-AUC, highlighting the utility …

Information-Seeking Preferences In Diverse Patients Receiving A Genetic Testing Result In The Clinical Sequencing Evidence-Generating Research (Cser) Study, Sarah Scollon, Shannon Rego, Tiffany Yip, Hannah Hoban, Kate M Foreman, Whitley Kelley, Candice Finnila, Jonathan Berg, Priyanka Murali, Katherine E Bonini, Lisa J Martin, Adam Hott

Faculty, Staff and Students Publications

Purpose: Accurate and understandable information after genetic testing is critical for patients, family members, and professionals alike.

Methods: As part of a cross-site study from the Clinical Sequencing Evidence-Generating Research consortium, we investigated the information-seeking practices among patients and family members at 5 to 7 months after genetic testing results disclosure, assessing the perceived utility of a variety of information sources, such as family and friends, health care providers, support groups, and the internet.

Results: We found that individuals placed a high value on information obtained from genetics professionals and health care workers, independent of genetic testing result case classifications …

Equine Bronchial Epithelial Cells Are Susceptible To Cell Entry With A Sars-Cov-2 Pseudovirus But Reveal Low Replication Efficiency, Bibiana Petri Da Silveira, Jennifer L Fridley, Kelsey M Wells, Numan Oezguen, Robert C Burghardt, Gus A Wright, Jeroen Pollet, Angela I Bordin, Paul De Figueiredo, Julian L Leibowitz, Noah D Cohen

Faculty, Staff and Students Publications

Objective: To examine the susceptibility of cultured primary equine bronchial epithelial cells (EBECs) to a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudovirus relative to human bronchial epithelial cells (HBECs).

Sample: Primary EBEC cultures established from healthy adult horses and commercially sourced human bronchial epithelial cells (HBECs) were used as a positive control.

Methods: Angiotensin-converting enzyme 2 (ACE2) expression by EBECs was demonstrated using immunofluorescence, western immunoblot, and flow cytometry. EBECs were transduced with a lentivirus pseudotyped with the SARS-CoV-2 spike protein that binds to ACE2 and expresses the enhanced green fluorescent protein (eGFP) as a reporter. Cells were transduced …

Analysis And Modeling Of Early Estradiol-Induced Greb1 Single Allele Gene Transcription At The Population Level, Ayse Koksoy, Michael A Mancini, Fabio Stossi, Robert Azencott

Faculty, Staff and Students Publications

Single molecule fluorescence in situ hybridization (smFISH) can be used to visualize transcriptional activation at the single allele level. We and others have applied this approach to better understand the mechanisms of activation by steroid nuclear receptors. However, there is limited understanding of the interconnection between the activation of target gene alleles inside the same nucleus and within large cell populations.

Using the GREB1 gene as an early estrogen receptor (ER) response target, we applied smFISH to track E2-activated GREB1 allelic transcription over early time points to evaluate potential dependencies between alleles within the same nucleus. We compared two types …

Alliance For Innovation On Maternal Health: Consensus Bundle On Sepsis In Obstetric Care., Melissa E Bauer, Catherine Albright, Malavika Prabhu, R Phillips Heine, Chelsea Lennox, Christie Allen, Carol Burke, April Chavez, Brenna L Hughes, Susan Kendig, Maile Le Boeuf, Elliott Main, Tiffany Messerall, Luis D Pacheco, Laura Riley, Rachel Solnick, Andrew Youmans, Ronald Gibbs

Women’s Health Articles

Sepsis in obstetric care is one of the leading causes of maternal death in the United States, with Black, Asian/Pacific Islander, and American Indian/Alaska Native obstetric patients experiencing sepsis at disproportionately higher rates. State maternal mortality review committees have determined that deaths are preventable much of the time and are caused by delays in recognition, treatment, and escalation of care. The "Sepsis in Obstetric Care" patient safety bundle provides guidance for health care teams to develop coordinated, multidisciplinary care for pregnant and postpartum people by preventing infection and recognizing and treating infection early to prevent progression to sepsis. This is …

Barriers And Facilitators Of Family Rules And Routines During Pediatric Cancer Treatment., Carolyn R. Bates, Isabella K. Pallotto, Rachel Moore, Lynne Covitz, Meredith Dreyer

Manuscripts, Articles, Book Chapters and Other Papers

OBJECTIVE: Pediatric nurses work closely with families of children with new cancer diagnoses and can provide essential supports to promote coping and adjustment. This cross-sectional qualitative study aimed to gather caregiver perspectives on barriers and facilitators to adaptive family functioning during the early phases of cancer treatment, with a focus on family rules and routines.

METHODS: Caregivers (N = 44) of a child diagnosed with cancer and receiving active treatment completed a semi-structured interview about their engagement in family rules and routines. Time since diagnosis was abstracted from the medical record. A multi-pass inductive coding strategy was utilized to extract …

The Two-Step Approach To Allogeneic Hematopoietic Stem Cell Transplantation, Sikemi Ibikunle, Dolores Grosso, Usama Gergis

Department of Medical Oncology Faculty Papers

Allogeneic hematopoietic stem cell transplantation (HSCT) provides the only potentially curative option for multiple hematological conditions. However, allogeneic HSCT outcomes rely on an optimal balance of effective immune recovery, minimal graft-versus-host disease (GVHD), and lasting control of disease. The quest to attain this balance has proven challenging over the past few decades. The two-step approach to HSCT was conceptualized and pioneered at Thomas Jefferson University in 2005 and remains the main platform for allografting at our institution. Following administration of the transplant conditioning regimen, patients receive a fixed dose of donor CD3+ cells (HSCT step one-DLI) as the lymphoid portion …

Stromal-Derived Nrg1 Enables Oncogenic Kras Bypass In Pancreas Cancer, Jincheng Han, Jiaqian Xu, Yonghong Liu, Shaoheng Liang, Kyle A Labella, Denise J Spring, Ronald A Depinho

Faculty, Staff and Student Publications

Activating KRAS mutations (KRAS*) in pancreatic ductal adenocarcinoma (PDAC) drive anabolic metabolism and support tumor maintenance. KRAS* inhibitors show initial antitumor activity followed by recurrence due to cancer cell-intrinsic and immune-mediated paracrine mechanisms. Here, we explored the potential role of cancer-associated fibroblasts (CAFs) in enabling KRAS* bypass and identified CAF-derived NRG1 activation of cancer cell ERBB2 and ERBB3 receptor tyrosine kinases as a mechanism by which KRAS*-independent growth is supported. Genetic extinction or pharmacological inhibition of KRAS* resulted in up-regulation of ERBB2 and ERBB3 expression in human and murine models, which prompted cancer cell utilization of CAF-derived NRG1 as a …

Antimicrobial Mitochondrial Reactive Oxygen Species Induction By Lung Epithelial Immunometabolic Modulation, Yongxing Wang, Vikram V Kulkarni, Jezreel Pantaleón García, Miguel M Leiva-Juárez, David L Goldblatt, Lisandra Vila Ellis, Michael K Longmire, Sri Ramya Donepudi, Philip L Lorenzi, Hao Wang, Lee-Jun Wong, Michael J Tuvim, Scott E Evans

Faculty, Staff and Student Publications

Pneumonia is a worldwide threat, making discovery of novel means to combat lower respiratory tract infection an urgent need. Manipulating the lungs' intrinsic host defenses by therapeutic delivery of certain pathogen-associated molecular patterns protects mice against pneumonia in a reactive oxygen species (ROS)-dependent manner. Here we show that antimicrobial ROS are induced from lung epithelial cells by interactions of CpG oligodeoxynucleotides (ODN) with mitochondrial voltage-dependent anion channel 1 (VDAC1). The ODN-VDAC1 interaction alters cellular ATP/ADP/AMP localization, increases delivery of electrons to the electron transport chain (ETC), increases mitochondrial membrane potential (ΔΨm), differentially modulates ETC complex activities and consequently results in …

Autotaxin Suppresses Cytotoxic T Cells Via Lpar5 To Promote Anti-Pd-1 Resistance In Non-Small Cell Lung Cancer, Jessica M Konen, B Leticia Rodriguez, Haoyi Wu, Jared J Fradette, Laura Gibson, Jing Wang, Ignacio I Wistuba, Jianjun Zhang, Don L Gibbons

Faculty, Staff and Student Publications

Non-small cell lung cancers that harbor concurrent KRAS and TP53 (KP) mutations are immunologically warm tumors with partial responsiveness to anti-PD-(L)1 blockade; however, most patients observe little or no durable clinical benefit. To identify novel tumor-driven resistance mechanisms, we developed a panel of KP murine lung cancer models with intrinsic resistance to anti-PD-1 and queried differential gene expression between these tumors and anti-PD-1-sensitive tumors. We found that the enzyme autotaxin (ATX), and the metabolite it produces, lysophosphatidic acid (LPA), were significantly upregulated in resistant tumors and that ATX directly modulated antitumor immunity, with its expression negatively correlating with total and …

Design Of A Phase Iii, Double-Blind, Randomised, Placebo-Controlled Trial Of Bi 1015550 In Patients With Progressive Pulmonary Fibrosis (Fibroneer-Ild), Toby M Maher, Shervin Assassi, Arata Azuma, Vincent Cottin, Anna-Maria Hoffmann-Vold, Justin M Oldham, Claudia Valenzuela, Marlies S Wijsenbeek, Carl Coeck, Christina Schlecker, Florian Voss, Daniel Wachtlin, Fernando J Martinez

Faculty, Staff and Student Publications

INTRODUCTION: Progressive pulmonary fibrosis (PPF) includes any diagnosis of progressive fibrotic interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis (IPF). However, disease progression appears comparable between PPF and IPF, suggesting a similar underlying pathology relating to pulmonary fibrosis. Following positive results in a phase II study in IPF, this phase III study will investigate the efficacy and safety of BI 1015550 in patients with PPF (FIBRONEER-ILD).

METHODS AND ANALYSIS: In this phase III, double-blind, placebo-controlled trial, patients are being randomised 1:1:1 to receive BI 1015550 (9 mg or 18 mg) or placebo twice daily over at least 52 weeks, …

Cellular And Metabolic Characteristics Of Pre-Leukemic Hematopoietic Progenitors With Gata2 Haploinsufficiency, Avigail Rein, Ifat Geron, Eitan Kugler, Hila Fishman, Eyal Gottlieb, Amir Giladi, Roger Mulet-Lazaro, Ruud Delwel, Stefan Gröschel, Smadar Levin-Zaidman, Nili Dezorella, Vered Holdengreber, Tata Nageswara Rao, Joanne Yacobovich, Orna Steinberg-Shemer, Qiu-Hua Huang, Yun Tan, Sai-Juan Chen, Shai Izraeli, Yehudit Birger

Faculty, Staff and Student Publications

Mono-allelic germline disruptions of the transcription factor GATA2 result in a propensity for developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), affecting more than 85% of carriers. How a partial loss of GATA2 functionality enables leukemic transformation years later is unclear. This question has remained unsolved mainly due to the lack of informative models, as Gata2 heterozygote mice do not develop hematologic malignancies. Here we show that two different germline Gata2 mutations (TgErg/Gata2het and TgErg/Gata2L359V) accelerate AML in mice expressing the human hematopoietic stem cell regulator ERG. Analysis of Erg/Gata2het fetal liver and bone marrow-derived hematopoietic cells revealed a …

Evaluating The Knowledge, Attitudes, And Practices Of Healthcare Workers Regarding High-Risk Nosocomial Infections: A Global Cross-Sectional Study, Elham M Khatrawi, Priyadarshi Prajjwal, Muhammad Farhan, Pugazhendi Inban, Shraddha Gurha, Mohammed D M Marsool, Mohammed A Mateen, Felix O Aina, Omniat A Hussin

Faculty, Staff and Student Publications

BACKGROUND: Healthcare workers (HCWs) play a vital role in delivering care and are frequently exposed to the risk of acquiring infections within the hospital setting. Around 15% of hospitalized patients suffer from these infections globally. However, the role and awareness of HCWs in the transmission of hospital-acquired infections (HAIs) or nosocomial infections is still unclear. This study aimed to evaluate the knowledge, attitude, and practices (KAP) toward high-risk microbial infections among HCWs on a global scale to identify measures to address this problem.

METHOD: A cross-sectional descriptive study was conducted between 2022 and 2023, with HCWs selected as the study …

Inhibition Of The Interaction Between Hippo/Yap And Akt Signaling With Ursolic Acid And 3’3-Diindolylmethane Suppresses Esophageal Cancer Tumorigenesis, Ruo Yu Meng, Cong Shan Li, Dan Hu, Soon-Gu Kwon, Hua Jin, Ju-Seog Lee

Faculty, Staff and Student Publications

Hippo/YAP signaling hinders cancer progression. Inactivation of this pathway contributes to the development of esophageal cancer by activation of Akt. However, the possible interaction between Akt and Hippo/YAP pathways in esophageal cancer progression is unclear. In this study, we found that ursolic acid (UA) plus 3'3-diindolylmethane (DIM) efficiently suppressed the oncogenic Akt/Gsk-3β signaling pathway while activating the Hippo tumor suppressor pathway in esophageal cancer cells. Moreover, the addition of the Akt inhibitor LY294002 and the PI3K inhibitor 3-methyladenine enhanced the inhibitory effects of UA plus DIM on Akt pathway activation and further stimulated the Hippo pathway, including the suppression of …