Medicine and Health Sciences Commons^™

Granulocytic Myeloid-Derived Suppressor Cell Activity During Biofilm Infection Is Regulated By A Glycolysis/Hif1a Axis, Christopher M. Horn, Prabhakar Arumugam, Zachary Van Roy, Cortney E. Heim, Rachel W. Fallet, Blake P. Bertrand, Dhananjay Shinde, Vinai Chittezham Thomas, Svetlana Romanova, Tatiana K. Bronich, Curtis Hartman, Kevin Garvin, Tammy Kielian

Journal Articles: Pathology and Microbiology

Staphylococcus aureus is a leading cause of biofilm-associated prosthetic joint infection (PJI). A primary contributor to infection chronicity is an expansion of granulocytic myeloid-derived suppressor cells (G-MDSCs), which are critical for orchestrating the antiinflammatory biofilm milieu. Single-cell sequencing and bioinformatic metabolic algorithms were used to explore the link between G-MDSC metabolism and S. aureus PJI outcome. Glycolysis and the hypoxia response through HIF1a were significantly enriched in G-MDSCs. Interfering with both pathways in vivo, using a 2-deoxyglucose nanopreparation and granulocyte-targeted Hif1a conditional KO mice, respectively, attenuated G-MDSC-mediated immunosuppression and reduced bacterial burden in a mouse model of S. aureus PJI. …

Metabolism Shapes Immune Responses To Staphylococcus Aureus., Prabhakar Arumugam, Tammy Kielian

Journal Articles: Pathology and Microbiology

BACKGROUND: Staphylococcus aureus (S. aureus) is a common cause of hospital- and community-acquired infections that can result in various clinical manifestations ranging from mild to severe disease. The bacterium utilizes different combinations of virulence factors and biofilm formation to establish a successful infection, and the emergence of methicillin- and vancomycin-resistant strains introduces additional challenges for infection management and treatment.

SUMMARY: Metabolic programming of immune cells regulates the balance of energy requirements for activation and dictates pro- versus anti-inflammatory function. Recent investigations into metabolic adaptations of leukocytes and S. aureus during infection indicate that metabolic crosstalk plays a crucial role in …

Metabolic Diversity Of Human Macrophages: Potential Influence On Staphylococcus Aureus Intracellular Survival, Blake P. Bertrand, Dhananjay Shinde, Vinai C. Thomas, Marvin Whiteley, Carolyn B. Ibberson, Tammy Kielian

Journal Articles: Pathology and Microbiology

Staphylococcus aureus is a leading cause of medical device-associated biofilm infections. This is influenced by the ability of S. aureus biofilm to evade the host immune response, which is partially driven by the anti-inflammatory cytokine interleukin-10 (IL-10). Here, we show that treatment of human monocyte-derived macrophages (HMDMs) with IL-10 enhanced biofilm formation, suggesting that macrophage anti-inflammatory programming likely plays an important role during the transition from planktonic to biofilm growth. To identify S. aureus genes that were important for intracellular survival in HMDMs and how this was affected by IL-10, transposon sequencing was performed. The size of the S. aureus …

The Impact Of Iron Supplementation On The Preterm Neonatal Gut Microbiome: A Pilot Study, Matthew Van Ormer, Maranda Thompson, Melissa Thoene, Jean-Jack Riethoven, Sathish Kumar Natarajan, Corrine K. Hanson, Ann Anderson-Berry

Journal Articles: Pediatrics

OBJECTIVE: The gastrointestinal microbiome in preterm infants exhibits significant influence on optimal outcomes-with dysbiosis shown to substantially increase the risk of the life-threatening necrotizing enterocolitis. Iron is a vital nutrient especially during the perinatal window of rapid hemoglobin production, tissue growth, and foundational neurodevelopment. However, excess colonic iron exhibits potent oxidation capacity and alters the gut microbiome-potentially facilitating the proliferation of pathological bacterial strains. Breastfed preterm infants routinely receive iron supplementation starting 14 days after delivery and are highly vulnerable to morbidities associated with gastrointestinal dysbiosis. Therefore, we set out to determine if routine iron supplementation alters the preterm gut …

Retinol And Pro-Vitamin A Carotenoid Nutritional Status During Pregnancy Is Associated With Newborn Hearing Screen Results, Rebecca Slotkowski, Matthew Van Ormer, Anum Akbar, Olivia Paetz, Taija Hahka, Maranda Thompson, Alyssa Freeman, Alexandra Hergenrader, Sarah Sweeney, Zeljka Korade, Thiago Genaro-Mattos, Corrine K. Hanson, Ann Anderson-Berry, Melissa K. Thoene

Journal Articles: Pediatrics

The prenatal period is critical for auditory development; thus, prenatal influences on auditory development may significantly impact long-term hearing ability. While previous studies identified a protective effect of carotenoids on adult hearing, the impact of these nutrients on hearing outcomes in neonates is not well understood. The purpose of this study is to investigate the relationship between maternal and umbilical cord plasma retinol and carotenoid concentrations and abnormal newborn hearing screen (NHS) results. Mother-infant dyads (n = 546) were enrolled at delivery. Plasma samples were analyzed using HPLC and LC-MS/MS. NHS results were obtained from medical records. Statistical analysis …

Plasma Retinol Concentrations And Dietary Intakes Of Mother-Infant Sets In Singleton Versus Twin Pregnancy, Anum Akbar, Sarah Duvall, Matthew Van Ormer, Rebecca Slotkowski, Taija Hahka, Thiago Genaro-Mattos, Zeljka Korade, Corrine K. Hanson, Ann Anderson-Berry, Melissa K. Thoene

Journal Articles: Pediatrics

Vitamin A (retinol) is essential for normal fetal development, but the recommendation for maternal dietary intake (Retinol Activity Equivalent, RAE) does not differ for singleton vs. twin pregnancy, despite the limited evaluation of retinol status. Therefore, this study aimed to evaluate plasma retinol concentrations and deficiency status in mother-infant sets from singleton vs. twin pregnancies as well as maternal RAE intake. A total of 21 mother-infant sets were included (14 singleton, 7 twin). The HPLC and LC-MS/HS evaluated the plasma retinol concentration, and data were analyzed using the Mann-Whitney U test. Plasma retinol was significantly lower in twin vs. singleton …

An International Real-World Analysis Of Relapsed/Refractory Lymphoma Occurring During Pregnancy, Faheem Farooq, Justin S. Brandt, Elyce Cardonick, Evgeniya Polushkina, Julie M. Vose, Sairah Ahmed, Praveen Ramakrishnan Geethakumari, Adam J. Olszewski, Hesham Yasin, Umar Farooq, Nada Hamad, Yong Lin, Charlotte Maggen, Robert Fruscio, Mina Mhallem Gziri, Karina Dahl Steffensen, Frédéric Amant, Andrew M. Evens

Journal Articles: Oncology and Hematology

No abstract provided.

The Salento Prognostic Model For Limited-Stage Peripheral T-Cell Lymphoma From The International T-Cell Project Network, Greg Hapgood, Monica Civallero, Yana Stepanishyna, Julie M. Vose, Monica Elena Cabrera, Ranjana H Advani, Stefano A. Pileri, Martina Manni, Steven M. Horwitz, Francine M. Foss, Felicitas Hitz, John Radford, Ivan Dlouhy, Carlos Chiattone, Won Seog Kim, Tetiana Skrypets, Arnon Nagler, Judith Trotman, Stefano Luminari, Massimo Federico

Journal Articles: Oncology and Hematology

The natural history of limited-stage peripheral T-cell lymphomas (PTCLs) remains poorly defined. We investigated outcomes and prognostic variables in patients registered in the T-Cell Project (TCP) (#NCT01142674) to develop a model to predict overall survival (OS) for the common nodal PTCL subtypes (PTCL-NOS, AITL, ALCL). The model was validated in an independent data set from Australian and Brazilian registries. 211 patients registered in the TCP between 2006-2018 were studied. The median age was 59 years (range 18-88) and median follow-up was 49 months. One hundred twenty-seven patients (78%) received anthracycline-based regimens, 5 patients (3%) radiotherapy alone (RT), 24 patients (15%) …

High-Grade B-Cell Lymphoma, Not Otherwise Specified: A Multi-Institutional Retrospective Study, Adam S. Zayac, Daniel J. Landsburg, Mitchell E. Hughes, Allison M. Bock, Grzegorz S. Nowakowski, Emily C. Ayers, Mark Girton, Marie Hu, Amy K. Beckman, Shaoying Li, L Jeffrey Medeiros, Julie E. Chang, Adam Stepanovic, Habibe Kurt, Jose Sandoval-Sus, M Ali Ansari-Lari, Shalin K. Kothari, Anna Kress, Mina L. Xu, Pallawi Torka, Suchitra Sundaram, Stephen D. Smith, Kikkeri N. Naresh, Yasmin H. Karimi, Narendranath Epperla, David A. Bond, Umar Farooq, Mahak Saad, Andrew M. Evens, Karan Pandya, Seema G. Naik, Manali Kamdar, Bradley Haverkos, Reem Karmali, Timothy S. Oh, Julie M. Vose, Heather Nutsch, Paul G. Rubinstein, Amina Chaudhry, Adam J. Olszewski

Journal Articles: Oncology and Hematology

In this multi-institutional retrospective study, we examined the characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS)-a rare category defined by high-grade morphologic features and lack of MYC rearrangements with BCL2 and/or BCL6 rearrangements ("double hit"). Our results show that HGBL-NOS tumors are heterogeneous: 83% of patients had a germinal center B-cell immunophenotype, 37% a dual-expressor immunophenotype (MYC and BCL2 expression), 28% MYC rearrangement, 13% BCL2 rearrangement, and 11% BCL6 rearrangement. Most patients presented with stage IV disease, a high serum lactate dehydrogenase, and other high-risk clinical factors. Most frequent first-line regimens included dose-adjusted cyclophosphamide, …

Integrative Analysis Of Clinicopathological Features Defines Novel Prognostic Models For Mantle Cell Lymphoma In The Immunochemotherapy Era: A Report From The North American Mantle Cell Lymphoma Consortium, Julie M. Vose, Kai Fu, Lu Wang, Adnan Mansoor, Douglas Stewart, Hongxia Cheng, Lynette M. Smith, Ji Yuan, Hina Naushad Qureishi, Brian K. Link, Melissa H. Cessna, Paul M. Barr, Brad S. Kahl, Matthew S. Mckinney, Nadia Khan, Ranjana H. Advani, Peter Martin, Andre H. Goy, Tycel J. Phillips, Amitkumar Mehta, Manali Kamdar, Michael Crump, Barbara Pro, Christopher R. Flowers, Caron A. Jacobson, Sonali M. Smith, Deborah M. Stephens, Veronika Bachanova, Zhaohui Jin, Shishou Wu, Francisco Hernandez-Ilizaliturri, Pallawi Torka, Andrea Anampa-Guzmán, Farshid Kashef, Xing Li, Sunandini Sharma, Timothy Greiner, James O. Armitage, Matthew A. Lunning, Dennis D. Weisenburger, Gregory Bociek, Javeed Iqbal, Guohua Yu, Chengfeng Bi, North American Mantle Cell Lymphoma Consortium

Journal Articles: Oncology and Hematology

BACKGROUND: Patients with mantle cell lymphoma (MCL) exhibit a wide variation in clinical presentation and outcome. However, the commonly used prognostic models are outdated and inadequate to address the needs of the current multidisciplinary management of this disease. This study aims to investigate the clinical and pathological features of MCL in the immunochemotherapy era and improve the prognostic models for a more accurate prediction of patient outcomes.

METHODS: The North American Mantle Cell Lymphoma Project is a multi-institutional collaboration of 23 institutions across North America to evaluate and refine prognosticators for front-line therapy. A total of 586 MCL cases diagnosed …

Molecular Characterization Of Streptococcus Pneumoniae Causing Disease Among Children In Nigeria During The Introduction Of Pcv10 (Gsk), Stephanie W. Lo, Paulina A. Hawkins, Binta Jibir, Fatimah Hassan-Hanga, Mahmoud Gambo, Rasaq Olaosebikan, Grace Olanipekun, Huda Munir, Nicholas Kocmich, Amy J. Rezac-Elgohary, Safiya Gambo, Danstan Bagenda, Paul D. Fey, Robert F. Breiman, Lesley Mcgee, Stephen D. Bentley, Stephen K. Obaro, Community Acquired Pneumonia And Invasive Bacterial Disease Capibd Consortium

Journal Articles: Anesthesiology

Streptococcus pneumoniae (pneumococcus) is a leading vaccine-preventable cause of childhood invasive disease. Nigeria has the second highest pneumococcal disease burden globally, with an estimated ~49 000 child deaths caused by pneumococcal infections each year. Ten-valent pneumococcal conjugate vaccine (GSK; PCV10) was introduced in December 2014 in a phased approach. However, few studies have characterized the disease-causing pneumococci from Nigeria. This study assessed the prevalence of serotypes, antibiotic susceptibility and genomic lineages using whole genome sequencing and identified lineages that could potentially escape PCV10 (GSK). We also investigated the potential differences in pneumococcal lineage features between children with and …

Novel Rna-Seq Signatures Post-Methamphetamine And Oxycodone Use In A Model Of Hiv-Associated Neurocognitive Disorders, Pranavi Athota, Nghi M. Nguyen, Victoria L. Schaal, Sankarasubramanian Jagadesan, Chittibabu Guda, Sowmya V. Yelamanchili, Gurudutt Pendyala

Journal Articles: Anesthesiology

In the 21st century, the effects of HIV-associated neurocognitive disorders (HAND) have been significantly reduced in individuals due to the development of antiretroviral therapies (ARTs). However, the growing epidemic of polysubstance use (PSU) has led to concern for the effects of PSU on HIV-seropositive individuals. To effectively treat individuals affected by HAND, it is critical to understand the biological mechanisms affected by PSU, including the identification of novel markers. To fill this important knowledge gap, we used an in vivo HIV-1 Transgenic (HIV-1 Tg) animal model to investigate the effects of the combined use of chronic methamphetamine (METH) and oxycodone …

Factors Associated With Prevalent Mycobacterium Tuberculosis Infection And Disease Among Adolescents And Adults Exposed To Rifampin-Resistant Tuberculosis In The Household, Soyeon Kim, Anneke C. Hesseling, Xingye Wu, Michael D. Hughes, N. Sarita Shah, Sanjay Gaikwad, Nishi Kumarasamy, Erika Mitchell, Mey Leon, Pedro Gonzales, Sharlaa Badal-Faesen, Madeleine Lourens, Sandy Nerette, Justin Shenje, Petra De Koker, Supalert Nedsuwan, Lerato Mohapi, Unoda A. Chakalisa, Rosie Mngqbisa, Rodrigo Otávio Da Silva Escada, Samuel Ouma, Barbara Heckman, Linda Naini, Amita Gupta, Susan Swindells, Gavin Churchyard, Actg A5300/Impaact 2003 Phoenix Feasibility Study Team

Journal Articles: Infectious Diseases

BACKGROUND: Understanding factors associated with prevalent Mycobacterium tuberculosis infection and prevalent TB disease in household contacts of patients with drug-resistant tuberculosis (TB) may be useful for TB program staff conducting contact investigations.

METHODS: Using data from a cross-sectional study that enrolled index participants with rifampin-resistant pulmonary TB and their household contacts (HHCs), we evaluated HHCs age ≥15 years for factors associated with two outcomes: Mycobacterium tuberculosis infection and TB disease. Among HHCs who were not already diagnosed with current active TB disease by the TB program, Mycobacterium tuberculosis infection was determined by interferon-gamma release assay (IGRA). TB disease was adjudicated …

Citrullinated And Malondialdehyde-Acetaldehyde Modified Fibrinogen Activates Macrophages And Promotes An Aggressive Synovial Fibroblast Phenotype In Patients With Rheumatoid Arthritis, Nozima Aripova, Michael J. Duryee, Bryant England, Carlos D. Hunter, Jack E. Mordeson, Evan Ryan, Eric C. Daubach, Debra J. Romberger, Geoffrey M. Thiele, Ted R. Mikuls

Journal Articles: Internal Medicine

Objective: Post-translational protein modifications with malondialdehyde-acetaldehyde (MAA) and citrulline (CIT) are implicated in the pathogenesis of rheumatoidarthritis (RA). Although precise mechanisms have not been elucidated, macrophage-fibroblast interactions have been proposed to play a central role in the development and progression of RA. The purpose of our study was to evaluate the downstream effects of macrophage released soluble mediators, following stimulation with fibrinogen (FIB) modified antigens, on human fibroblast-like synoviocytes (HFLS).

Methods: PMA-treated U-937 monocytes (Mϕ) and macrophage-differentiated peripheral blood mononuclear cells (MP) were stimulated with FIB, FIB-MAA, FIB-CIT, or FIB-MAA-CIT. HFLS-RA cells were stimulated directly with FIB antigens or with …

An Intravenous Pancreatic Cancer Therapeutic: Characterization Of Crispr/Cas9n-Modified Clostridium Novyi-Non Toxic, Kaitlin M. Dailey, James M. Small, Jessica E. Pullan, Seth Winfree, Krysten E. Vance, Megan Orr, Sanku Mallik, Kenneth W. Bayles, Michael A. Hollingsworth, Amanda E Brooks

Journal Articles: Pathology and Microbiology

Clostridium novyi has demonstrated selective efficacy against solid tumors largely due to the microenvironment contained within dense tumor cores. The core of a solid tumor is typically hypoxic, acidic, and necrotic-impeding the penetration of current therapeutics. C. novyi is attracted to the tumor microenvironment and once there, can both lyse and proliferate while simultaneously re-activating the suppressed immune system. C. novyi systemic toxicity is easily mitigated by knocking out the phage DNA plasmid encoded alpha toxin resulting in C. novyi-NT; but, after intravenous injection spores are quickly cleared by phagocytosis before accomplishing significant tumor localization. C. novyi-NT could be designed …

Androgen Receptor Inhibition Suppresses Anti-Tumor Neutrophil Response Against Bone Metastatic Prostate Cancer Via Regulation Of Tβri Expression, Massar Alsamraae, Diane Costanzo-Garvey, Benjamin A. Teply, Shawna Boyle, Gary Sommerville, Zachary T. Herbert, Colm Morrissey, Alicia J. Dafferner, Maher Y. Abdalla, Rachel W. Fallet, Tammy Kielian, Heather Jensen Smith, Edson I. Deoliveira, Keqiang Chen, Ian A. Bettencourt, Ji Ming Wang, Daniel W. Mcvicar, Tyler Keeley, Fang Yu, Leah M. Cook

Journal Articles: Pathology and Microbiology

Bone metastatic disease of prostate cancer (PCa) is incurable and progression in bone is largely dictated by tumor-stromal interactions in the bone microenvironment. We showed previously that bone neutrophils initially inhibit bone metastatic PCa growth yet metastatic PCa becomes resistant to neutrophil response. Further, neutrophils isolated from tumor-bone lost their ability to suppress tumor growth through unknown mechanisms. With this study, our goal was to define the impact of metastatic PCa on neutrophil function throughout tumor progression and to determine the potential of neutrophils as predictive biomarkers of metastatic disease. Using patient peripheral blood polymorphonuclear neutrophils (PMNs), we identified that …

Agricultural Dust Derived Bacterial Extracellular Vesicle Mediated Inflammation Is Attenuated By Dha, Art J. Heires, Derrick R. Samuelson, Daniel Villageliu, Tara M. Nordgren, Debra J. Romberger

Journal Articles: Pulmonary & Critical Care Med

Dietary long-chain omega-3 polyunsaturated fatty acids (n-3 PUFA) and their pro-resolving metabolites are protective against atherosclerotic disease, and ameliorate systemic inflammatory conditions including lupus erythematosus, psoriasis, and bronchial asthma. Organic bioaerosol inhalation is a common and injurious hazard associated with agricultural occupations such as work in swine concentrated animal feeding operations (CAFOs) and is known to increase the risk for developing respiratory conditions such as asthma and COPD. Nearly all cells secrete membrane-bound vesicles (extracellular vesicles, EVs) that have the capacity to transmit protein, nucleic acid, and lipid signaling mediators between cells. Using a polymer-based isolation technique (ExoQuick, PEG) followed …

Omega-3 Polyunsaturated Fatty Acid Levels In Maternal And Cord Plasma Are Associated With Maternal Socioeconomic Status, Alexandra Hergenrader, Matthew Van Ormer, Rebecca Slotkowski, Maranda Thompson, Alyssa Freeman, Olivia Paetz, Sarah Sweeney, Lauren Wegner, Khadijjta Ali, Nicole S. Bender, Ridhi Chaudhary, Melissa K. Thoene, Corrine K. Hanson, Ann Anderson-Berry

Journal Articles: Pediatrics

Omega-3 (n-3) polyunsaturated fatty acids (PUFAs) play a crucial role in fetal growth and neurodevelopment, while omega-6 (n-6) PUFAs have been associated with adverse pregnancy outcomes. Previous studies have demonstrated that socioeconomic status (SES) influences dietary intake of n-3 and n-6 PUFAs, but few studies have evaluated the association between maternal and cord plasma biomarkers of PUFAs and socioeconomic markers. An IRB-approved study enrolled mother-infant pairs (n = 55) at the time of delivery. Maternal and cord plasma PUFA concentrations were analyzed using gas chromatography. Markers of SES were obtained from validated surveys …

Nutrition Support Practices For Infants Born <750 Grams Or <25 Weeks Gestation: A Call For More Research, Melissa K. Thoene, Ann Anderson-Berry

Journal Articles: Pediatrics

With advances in medical care and efforts to care for continually smaller and younger preterm infants, the gestational age of viability has decreased, including as young as 21 or 22 weeks of gestation [...].

Postoperative Breath-Holding Spells Requiring Cardiopulmonary Resuscitation After Cardiopulmonary Bypass, Rebecca Kreis, Jeffrey A. Robinson, Ali N. Ibrahimiye, Laura Ortmann

Journal Articles: Pediatrics

Breath-holding spells are common in childhood and can be associated with bradycardia and pulselessness. This report details severe breath-holding spells complicating postoperative management after atrial septal defect closure. The patient required cardiopulmonary resuscitation despite the use of a temporary pacemaker to prevent bradycardia. After multiple episodes of chest compressions, the decision was made to not intervene immediately to pulselessness and the patient was able to recover without further intervention.

Caregiver Willingness To Give Tpt To Children Living With Drug-Resistant Tb Patients, V. Rouzier, M. Murrill, S. Kim, L. Naini, J. Shenje, E. Mitchell, M. Raesi, M. Lourens, A. Mendoza, F. Conradie, N. Suryavanshi, M. Hughes, S. Shah, G. Churchyard, Susan Swindells, A. Hesseling, A. Gupta

Journal Articles: Infectious Diseases

Pediatric household contacts (HHCs) of patients with multidrug-resistant TB (MDR-TB) are at high risk of infection and active disease. Evidence of caregiver willingness to give MDR-TB preventive therapy (TPT) to children is limited.METHODS This was a cross-sectional study of HHCs of patients with MDR-TB to assess caregiver willingness to give TPT to children aged <13 years.RESULTS Of 743 adult and adolescent HHCs, 299 reported caring for children aged <13 years of age. The median caregiver age was 35 years (IQR 27-48); 75% were women. Among caregivers, 89% were willing to give children MDR TPT. In unadjusted analyses, increased willingness was associated with TB-related knowledge (OR 5.1, 95% CI 2.3-11.3), belief that one can die of MDR-TB (OR 5.2, 95% CI 1.2-23.4), concern for MDR-TB transmission to child (OR 4.5, 95% CI 1.6-12.4), confidence in properly taking TPT (OR 4.5, 95% CI 1.6-12.6), comfort telling family about TPT (OR 5.5, 95% CI 2.1-14.3), and willingness to take TPT oneself (OR 35.1, 95% CI 11.0-112.8).CONCLUSIONS A high percentage of caregivers living with MDR- or rifampicin-resistant TB patients were willing to give children a hypothetical MDR TPT. These results provide important evidence for the potential uptake of …

Machine Learning Analyses Of Highly-Multiplexed Immunofluorescence Identifies Distinct Tumor And Stromal Cell Populations In Primary Pancreatic Tumors, Krysten Vance, Alphan Alitinok, Seth Winfree, Heather Jensen Smith, Benjamin Swanson Md, Phd, Paul M. Grandgenett, Kelsey Klute, Daniel J Crichton, Michael A. Hollingsworth

Journal Articles: Eppley Institute

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a formidable challenge for patients and clinicians.

OBJECTIVE: To analyze the distribution of 31 different markers in tumor and stromal portions of the tumor microenvironment (TME) and identify immune cell populations to better understand how neoplastic, non-malignant structural, and immune cells, diversify the TME and influence PDAC progression.

METHODS: Whole slide imaging (WSI) and cyclic multiplexed-immunofluorescence (MxIF) was used to collect 31 different markers over the course of nine distinctive imaging series of human PDAC samples. Image registration and machine learning algorithms were developed to largely automate an imaging analysis pipeline identifying distinct cell …

Modified Chitosan For Effective Renal Delivery Of Sirna To Treat Acute Kidney Injury., Weimin Tang, Chinmay M. Jogdeo, Sudipta Panja, Siyuan Tang, Ling Ding, Ao Yu, Kirk W. Foster, Del L. Dsouza, Yashpal S. Chhonker, Heather Jensen Smith, Hee-Seong Jang, Erika I. Boesen, Daryl J. Murry, Babu Padanilam, David Oupicky

Journal Articles: Eppley Institute

Acute kidney injury (AKI) is characterized by a sudden decrease in renal function and impacts growing number of people worldwide. RNA interference (RNAi) showed potential to treat diseases with no or limited conventional therapies, including AKI. Suitable carriers are needed to protect and selectively deliver RNAi to target cells to fully explore this therapeutic modality. Here, we report on the synthesis of chitosan modified with α-cyclam-p-toluic acid (C-CS) as a novel siRNA carrier for targeted delivery to injured kidneys. We demonstrate that conjugation of the α-cyclam-p-toluic acid to chitosan imparts the C-CS polymer with targeting and antagonistic properties to cells …

Insect Cell Expression And Purification Of Recombinant Sars-Cov-2 Spike Proteins That Demonstrate Ace2 Binding, Lucas R. Struble, Audrey L. Smith, William E. Lutz, Gabrielle Grubbs, Satish Sagar, Kenneth W. Bayles, Prakash Radhakrishnan, Surender Khurana, Dalia El-Gamal, Gloria E. O. Borgstahl

Journal Articles: Pathology and Microbiology

The COVID-19 pandemic caused by SARS-CoV-2 infection has led to socio-economic shutdowns and the loss of over 5 million lives worldwide. There is a need for the identification of therapeutic targets to treat COVID-19. SARS-CoV-2 spike is a target of interest for the development of therapeutic targets. We developed a robust SARS-CoV-2 S spike expression and purification protocol from insect cells and studied four recombinant SARS-CoV-2 spike protein constructs based on the original SARS-CoV-2 sequence using a baculovirus expression system: a spike protein receptor-binding domain that includes the SD1 domain (RBD) coupled to a fluorescent tag (S-RBD-eGFP), spike ectodomain coupled …

Type I Ifn Signaling Protects Mice From Lethal Sars-Cov-2 Neuroinvasion., Md Bashir Uddin, Yuejin Liang, Shengjun Shao, Sunil Palani, Michael Mckelvey, Scott C. Weaver, Keer Sun

Journal Articles: Pathology and Microbiology

Multiple organ damage is common in patients with severe COVID-19, even though the underlying pathogenic mechanisms remain unclear. Acute viral infection typically activates type I IFN (IFN-I) signaling. The antiviral role of IFN-I is well characterized in vitro. However, our understanding of how IFN-I regulates host immune response to SARS-CoV-2 infection in vivo is incomplete. Using a human ACE2-transgenic mouse model, we show in the present study that IFN-I receptor signaling is essential for protection against the acute lethality of SARS-CoV-2 in mice. Interestingly, although IFN-I signaling limits viral replication in the lung, the primary infection site, it is dispensable …

Ifn-Γ Transforms The Transcriptomic Landscape And Triggers Myeloid Cell Hyperresponsiveness To Cause Lethal Lung Injury, Atul K. Verma, Michael Mckelvey, Md Bashir Uddin, Sunil Palani, Meng Niu, Christopher Bauer, Shengjun Shao, Keer Sun

Journal Articles: Pathology and Microbiology

Acute Respiratory Distress Syndrome (ARDS) is an inflammatory disease that is associated with high mortality but no specific treatment. Our understanding of initial events that trigger ARDS pathogenesis is limited. We have developed a mouse model of inflammatory lung injury by influenza and methicillin-resistant Staphylococcus aureus (MRSA) coinfection plus daily antibiotic therapy. Using this pneumonic ARDS model, here we show that IFN-γ receptor signaling drives inflammatory cytokine storm and lung tissue damage. By single-cell RNA sequencing (scRNA-seq) analysis, we demonstrate that IFN-γ signaling induces a transcriptional shift in airway immune cells, particularly by upregulating macrophage and monocyte expression of genes …

Relationships Of Serum Cc16 Levels With Smoking Status And Lung Function In Copd, Kelli C. Gribben, Jill A. Poole, Amy J. Nelson, Paraskevi A. Farazi, Christopher S. Wichman, Art J. Heires, Debra J. Romberger, Tricia D. Levan

Journal Articles: Pulmonary & Critical Care Med

Background: The club cell secretory protein (CC16) has anti-inflammatory and antioxidant effects, and low CC16 serum levels have been associated with both risk and progression of COPD, yet the interaction between smoking and CC16 on lung function outcomes remains unknown.

Methods: Utilizing cross-sectional data on United States veterans, CC16 serum concentrations were measured by ELISA and log transformed for analyses. Spirometry was conducted and COPD status was defined by post-bronchodilator FEV₁/FVC ratio < 0.7. Smoking measures were self-reported on questionnaire. Multivariable logistic and linear regression were employed to examine associations between CC16 levels and COPD, and lung function with adjustment for covariates. Unadjusted Pearson correlations described relationships between CC16 level and lung function measures, pack-years smoked, and years since smoking cessation.

Results: The study population (N = 351) was mostly male, white, with an average age over 60 years. An interaction between CC16 and smoking status on …

Clinical Laboratory Testing Practices In Diffuse Gliomas Prior To Publication Of 2021 World Health Organization Classification Of Central Nervous System Tumors, Shakti H. Ramkissoon, Helen Fernandes, Dolores H. Lopez-Terrada, Meera R. Hameed, Dimitri G. Trembath, Julia A. Bridge, Neal I. Lindeman, Rhona J. Souers, Patricia Vasalos, Daniel J Brat, Joel T. Moncur

Journal Articles: Pathology and Microbiology

CONTEXT.—: Integration of molecular data into glioma classification supports diagnostic, prognostic, and therapeutic decision-making; however, testing practices for these informative biomarkers in clinical laboratories remain unclear.

OBJECTIVE.—: To examine the prevalence of molecular testing for clinically relevant biomarkers in adult and pediatric gliomas through review of a College of American Pathologists proficiency testing survey prior to the release of the 2021 World Health Organization Classification of Central Nervous System Tumors.

DESIGN.—: College of American Pathologists proficiency testing 2020 survey results from 96 laboratories performing molecular testing for diffuse gliomas were used to determine the use of testing for molecular biomarkers …

Drug Susceptibility Patterns Of Mycobacterium Tuberculosis From Adults With Multidrug-Resistant Tuberculosis And Implications For A Household Contact Preventive Therapy Trial, Anne-Marie Demers, Soyeon Kim, Sara Mccallum, Kathleen Eisenach, Michael Hughes, Linda Naini, Alberto Mendoza-Ticona, Neeta Pradhan, Kim Narunsky, Selvamuthu Poongulali, Sharlaa Badal-Faesen, Caryn Upton, Elizabeth Smith, N Sarita Shah, Gavin Churchyard, Amita Gupta, Anneke Hesseling, Susan Swindells, Actg A5300/Impaact I2003 Phoenix Feasibility Study Team

Journal Articles: Internal Medicine

BACKGROUND: Drug susceptibility testing (DST) patterns of Mycobacterium tuberculosis (MTB) from patients with rifampicin-resistant tuberculosis (RR-TB) or multidrug-resistant TB (MDR-TB; or resistant to rifampicin and isoniazid (INH)), are important to guide preventive therapy for their household contacts (HHCs).

METHODS: As part of a feasibility study done in preparation for an MDR-TB preventive therapy trial in HHCs, smear, Xpert MTB/RIF, Hain MTBDRplus, culture and DST results of index MDR-TB patients were obtained from routine TB programs. A sputum sample was collected at study entry and evaluated by the same tests. Not all tests were performed on all specimens due to variations …

Child Health And The Implementation Of Community And District-Management Empowerment For Scale-Up (Codes) In Uganda: A Randomised Controlled Trial, Peter Waiswa, Flavia Mpanga, Danstan Bagenda, Rornald Muhumuza Kananura, Thomas O'Connell, Dorcus Kiwanuka Henriksson, Theresa Diaz, Florence Ayebare, Anne Ruhweza Katahoire, Eric Ssegujja, Anthony Mbonye, Stefan Swartling Peterson

Journal Articles: Anesthesiology

INTRODUCTION: Uganda's district-level administrative units buttress the public healthcare system. In many districts, however, local capacity is incommensurate with that required to plan and implement quality health interventions. This study investigates how a district management strategy informed by local data and community dialogue influences health services.

METHODS: A 3-year randomised controlled trial (RCT) comprised of 16 Ugandan districts tested a management approach, Community and District-management Empowerment for Scale-up (CODES). Eight districts were randomly selected for each of the intervention and comparison areas. The approach relies on a customised set of data-driven diagnostic tools to identify and resolve health system bottlenecks. …