Pathology Commons^™

Fluorescent Sensor Arrays Can Predict And Quantify The Composition Of Multicomponent Bacterial Samples, Denis Svechkarev, Marat Sadykov, Lucas J. Houser, Kenneth W. Bayles, Aaron M. Mohs

Journal Articles: Pathology and Microbiology

Fast and reliable identification of infectious disease agents is among the most important challenges for the healthcare system. The discrimination of individual components of mixed infections represents a particularly difficult task. In the current study we further expand the functionality of a ratiometric sensor array technology based on small-molecule environmentally-sensitive organic dyes, which can be successfully applied for the analysis of mixed bacterial samples. Using pattern recognition methods and data from pure bacterial species, we demonstrate that this approach can be used to quantify the composition of mixtures, as well as to predict their components with the accuracy of ~80% …

Stochastic Expression Of Sae-Dependent Virulence Genes During Staphylococcus Aureus Biofilm Development Is Dependent On Saes, Elizabeth A. Delmain, Derek E. Moormeier, Jennifer L. Endres, Rebecca E. Hodges, Marat R. Sadykov, Alexander R. Horswill, Kenneth W. Bayles

Journal Articles: Pathology and Microbiology

The intricate process of biofilm formation in the human pathogen Staphylococcus aureus involves distinct stages during which a complex mixture of matrix molecules is produced and modified throughout the developmental cycle. Early in biofilm development, a subpopulation of cells detaches from its substrate in an event termed “exodus” that is mediated by SaePQRS-dependent stochastic expression of a secreted staphylococcal nuclease, which degrades extracellular DNA within the matrix, causing the release of cells and subsequently allowing for the formation of metabolically heterogenous microcolonies. Since the SaePQRS regulatory system is involved in the transcriptional control of multiple S. aureus virulence factors, the …

Neutrophils Are Mediators Of Metastatic Prostate Cancer Progression In Bone, Diane L. Costanzo-Garvey, Tyler Keeley, Adam J. Case, Gabrielle F. Watson, Massar Alsamraae, Yangsheng Yu, Kaihong Su, Cortney E. Heim, Tammy Kielian, Colm Morrissey, Jeremy S Frieling, Leah M. Cook

Journal Articles: Pathology and Microbiology

Bone metastatic prostate cancer (BM-PCa) significantly reduces overall patient survival and is currently incurable. Current standard immunotherapy showed promising results for PCa patients with metastatic, but less advanced, disease (i.e., fewer than 20 bone lesions) suggesting that PCa growth in bone contributes to response to immunotherapy. We found that: (1) PCa stimulates recruitment of neutrophils, the most abundant immune cell in bone, and (2) that neutrophils heavily infiltrate regions of prostate tumor in bone of BM-PCa patients. Based on these findings, we examined the impact of direct neutrophil-prostate cancer interactions on prostate cancer growth. Bone marrow neutrophils directly induced apoptosis …

Tlr2 And Caspase-1 Signaling Are Critical For Bacterial Containment But Not Clearance During Craniotomy-Associated Biofilm Infection, Amy L. Aldrich, Cortney E. Heim, Wen Shi, Rachel W. Fallet, Bin Duan, Tammy Kielian

Journal Articles: Pathology and Microbiology

BACKGROUND: A craniotomy is required to access the brain for tumor resection or epilepsy treatment, and despite precautionary measures, infectious complications occur at a frequency of 1-3%. Approximately half of craniotomy infections are caused by Staphylococcus aureus (S. aureus) that forms a biofilm on the bone flap, which is recalcitrant to antibiotics. Our prior work in a mouse model of S. aureus craniotomy infection revealed a critical role for myeloid differentiation factor 88 (MyD88) in bacterial containment and pro-inflammatory mediator production. Since numerous receptors utilize MyD88 as a signaling adaptor, the current study examined the importance of Toll-like receptor 2 …

An Integrated Computational And Experimental Study To Investigate Staphylococcus Aureus Metabolism, Mohammad Mazharul Islam, Vinai Chittezham Thomas, Matthew Van Beek, Jong-Sam Ahn, Abdulelah A. Alqarzaee, Chunyi Zhou, Paul D. Fey, Kenneth W. Bayles, Rajib Saha

Journal Articles: Pathology and Microbiology

Staphylococcus aureus is a metabolically versatile pathogen that colonizes nearly all organs of the human body. A detailed and comprehensive knowledge of staphylococcal metabolism is essential to understand its pathogenesis. To this end, we have reconstructed and experimentally validated an updated and enhanced genome-scale metabolic model of S. aureus USA300_FPR3757. The model combined genome annotation data, reaction stoichiometry, and regulation information from biochemical databases and previous strain-specific models. Reactions in the model were checked and fixed to ensure chemical balance and thermodynamic consistency. To further refine the model, growth assessment of 1920 nonessential mutants from the Nebraska Transposon Mutant Library …

Monocyte Metabolic Reprogramming Promotes Pro-Inflammatory Activity And Staphylococcus Aureus Biofilm Clearance, Kelsey J. Yamada, Cortney E. Heim, Xinyuan Xi, Kuldeep S. Attri, Dezhen Wang, Wenting Zhang, Pankaj K. Singh, Tatiana K. Bronich, Tammy Kielian

Journal Articles: Pathology and Microbiology

Biofilm-associated prosthetic joint infections (PJIs) cause significant morbidity due to their recalcitrance to immune-mediated clearance and antibiotics, with Staphylococcus aureus (S. aureus) among the most prevalent pathogens. We previously demonstrated that S. aureus biofilm-associated monocytes are polarized to an anti-inflammatory phenotype and the adoptive transfer of pro-inflammatory macrophages attenuated biofilm burden, highlighting the critical role of monocyte/macrophage inflammatory status in dictating biofilm persistence. The inflammatory properties of leukocytes are linked to their metabolic state, and here we demonstrate that biofilm-associated monocytes exhibit a metabolic bias favoring oxidative phosphorylation (OxPhos) and less aerobic glycolysis to facilitate their anti-inflammatory activity and biofilm …

Sarcoidosis Of The Mandibular Condyle: A Rare Disease That Can Mimic Malignancy, Chad Sloan, Ben Lacrosse, Lei Yu, Alexander Braun, Scott Lauer, Timothy Donovan, John Baker, Jason Untrauer

Graduate Medical Education Research Journal

Sarcoidosis can involve any of the organs, however intraosseous involvement is rare and ranges from 5 to 15%, with lesions of the mandible being even rarer – currently with few known cases reported. Intraosseous lesions involving the mandible have been noted to be asymptomatic or associated with chronic jaw pain. Additionally, mandibular involvement can present as a lytic bone lesion mimicking osseous malignancy. Chronic polyarthritis is commonly associated with the progression of sarcoidosis and intraosseous involvement has been considered a late-stage sequelae. We report a case of biopsy-proven sarcoidosis within the mandibular condyle in an asymptomatic 56-year-old Caucasian female who …

Reanalysis Of The Nccn Pd-L1 Companion Diagnostic Assay Study For Lung Cancer In The Context Of Pd-L1 Expression Findings In Triple-Negative Breast Cancer, David L. Rimm, Gang Han, Janis M. Taube, Eunhee S. Yi, Julia A. Bridge, Douglas B. Flieder, Robert Homer, Anja C. Roden, Fred R. Hirsch, Ignacio I. Wistuba, Lajos Pusztai

Journal Articles: Pathology and Microbiology

The companion diagnostic test for checkpoint inhibitor immune therapy is an immunohistochemical test for PD-L1. The test has been shown to be reproducible for expression in tumor cells, but not in immune cells. Immune cells were used in the IMpassion130 trial which showed PD-L1 expression was associated with a better outcome. Two large studies have been done assessing immune cell PD-L1 expression in lung cancer. Here, we reanalyze one of those studies, to show that, even with an easier scoring method, there is still only poor agreement between assays and pathologist for immune cell PD-L1 expression.

Observations Of Shear Stress Effects On Staphylococcus Aureus Biofilm Formation, Erica Sherman, Kenneth W. Bayles, Derek E. Moormeier, Jennifer L. Endres, Timothy Wei

Journal Articles: Pathology and Microbiology

Staphylococcus aureus bacteria form biofilms and distinctive microcolony or "tower" structures that facilitate their ability to tolerate antibiotic treatment and to spread within the human body. The formation of microcolonies, which break off, get carried downstream, and serve to initiate biofilms in other parts of the body, is of particular interest here. It is known that flow conditions play a role in the development, dispersion, and propagation of biofilms in general. The influence of flow on microcolony formation and, ultimately, what factors lead to microcolony development are, however, not well understood. The hypothesis being examined is that microcolony structures form …

Urease Is An Essential Component Of The Acid Response Network Of Staphylococcus Aureus And Is Required For A Persistent Murine Kidney Infection, Chunyi Zhou, Fatema Bhinderwala, Mckenzie K. Lehman, Vinai Chittezham Thomas, Sujata S. Chaudhari, Kelsey J. Yamada, Kirk W. Foster, Robert Powers, Tammy Kielian, Paul D. Fey

Journal Articles: Pathology and Microbiology

Staphylococcus aureus causes acute and chronic infections resulting in significant morbidity. Urease, an enzyme that generates NH3 and CO2 from urea, is key to pH homeostasis in bacterial pathogens under acidic stress and nitrogen limitation. However, the function of urease in S. aureus niche colonization and nitrogen metabolism has not been extensively studied. We discovered that urease is essential for pH homeostasis and viability in urea-rich environments under weak acid stress. The regulation of urease transcription by CcpA, Agr, and CodY was identified in this study, implying a complex network that controls urease expression in response to changes in metabolic …

Protease-Mediated Growth Of Staphylococcus Aureus On Host Proteins Is Opp3 Dependent, Mckenzie K. Lehman, Austin S. Nuxoll, Kelsey J. Yamada, Tammy Kielian, Steven D. Carson, Paul D. Fey

Journal Articles: Pathology and Microbiology

Staphylococcus aureus has the ability to cause infections in multiple organ systems, suggesting an ability to rapidly adapt to changing carbon and nitrogen sources. Although there is little information about the nutrients available at specific sites of infection, a mature skin abscess has been characterized as glucose depleted, indicating that peptides and free amino acids are an important source of nutrients for the bacteria. Our studies have found that mutations in enzymes necessary for growth on amino acids, including pyruvate carboxykinase (ΔpckA) and glutamate dehydrogenase (ΔgudB), reduced the ability of the bacteria to proliferate within a …

Identification Of Extracellular Dna-Binding Proteins In The Biofilm Matrix., Jeffrey S. Kavanaugh, Caralyn E. Flack, Jessica Lister, Erica B. Ricker, Carolyn B. Ibberson, Christian Jenul, Derek E. Moormeier, Elizabeth A. Delmain, Kenneth W. Bayles, Alexander R. Horswill

Journal Articles: Pathology and Microbiology

We developed a new approach that couples Southwestern blotting and mass spectrometry to discover proteins that bind extracellular DNA (eDNA) in bacterial biofilms. Using Staphylococcus aureus as a model pathogen, we identified proteins with known DNA-binding activity and uncovered a series of lipoproteins with previously unrecognized DNA-binding activity. We demonstrated that expression of these lipoproteins results in an eDNA-dependent biofilm enhancement. Additionally, we found that while deletion of lipoproteins had a minimal impact on biofilm accumulation, these lipoprotein mutations increased biofilm porosity, suggesting that lipoproteins and their associated interactions contribute to biofilm structure. For one of the lipoproteins, SaeP, we …

Oligomerization Of Bacterially Expressed H1n1 Recombinant Hemagglutinin Contributes To Protection Against Viral Challenge, Tess E. Kuenstling, Anthony R. Sambol, Steven H. Hinrichs, Marilynn A. Larson

Journal Articles: Pathology and Microbiology

Vaccination is the most effective intervention to prevent influenza and control the spread of the virus. Alternatives are needed to the traditional egg-based vaccine strategy for a more rapid response to new outbreaks. Two different hemagglutinin (HA) fragments (rHA1_1-326 and rHA1_53-269) derived from influenza A virus subtype H1N1 were expressed in Escherichia coli and characterized by immunoblot, gel filtration, hemagglutination, and competitive binding assays. rHA1_1-326 included neutralizing epitopes and the trimerization domain, whereas rHA1_53-269 included only the head of HA with the neutralizing epitopes. Mice were immunized with rHA1_1-326 or rHA1_53-269, and …

Searching For Novel Biomarkers Using A Mouse Model Of Cln3-Batten Disease, Derek Timm, Jacob T. Cain, Ryan D. Geraets, Katherine A. White, Seung Yon Koh, Tammy Kielian, David A. Pearce, Michelle L. Hastings, Jill M. Weimer

Journal Articles: Pathology and Microbiology

CLN3-Batten disease is a rare, autosomal recessive disorder involving seizures, visual, motor and cognitive decline, and premature death. The Cln3Δex7/8 mouse model recapitulates several phenotypic characteristics of the most common 1.02kb disease-associated deletion. Identification of reproducible biomarker(s) to facilitate longitudinal monitoring of disease progression and provide readouts for therapeutic response has remained elusive. One factor that has complicated the identification of suitable biomarkers in this mouse model has been that variations in animal husbandry appear to significantly influence readouts. In the current study, we cross-compared a number of biological parameters in blood from Cln3Δex7/8 mice and control, non-disease mice on …

Novel Long-Chain Compounds With Both Immunomodulatory And Mena Inhibitory Activities Against Staphylococcus Aureus And Its Biofilm., Seoung-Ryoung Choi, Joel Frandsen, Prabagaran Narayanasamy

Journal Articles: Pathology and Microbiology

Menaquinone (MK) biosynthesis pathway is a potential target for evaluating antimicrobials in gram-positive bacteria. Here, 1,4-dihydroxy-2-naphthoate prenyltransferase (MenA) was targeted to reduce methicillin-resistant Staphylococcus aureus (MRSA) growth. MenA inhibiting, long chain-based compounds were designed, synthesized and evaluated against MRSA and menaquinone utilizing bacteria in aerobic conditions. The results showed that these bacteria were susceptible to most of the compounds. Menaquinone (MK-4) supplementation rescued MRSA growth, suggesting these compounds inhibit MK biosynthesis. 3a and 7c exhibited promising inhibitory activities with MICs ranging 1-8 μg/mL against MRSA strains. The compounds did not facilitate small colony variant formation. These compounds also inhibited the …

Neuroprotection Through Flavonoid: Enhancement Of The Glyoxalase Pathway., Joel Frandsen, Prabagaran Narayanasamy

Journal Articles: Pathology and Microbiology

The glyoxalase pathway functions to detoxify reactive dicarbonyl compounds, most importantly methylglyoxal. The glyoxalase pathway is an antioxidant defense mechanism that is essential for neuroprotection. Excessive concentrations of methylglyoxal have deleterious effects on cells, leading to increased levels of inflammation and oxidative stress. Neurodegenerative diseases - including Alzheimer's, Parkinson's, Aging and Autism Spectrum Disorder - are often induced or exacerbated by accumulation of methylglyoxal. Antioxidant compounds possess several distinct mechanisms that enhance the glyoxalase pathway and function as neuroprotectants. Flavonoids are well-researched secondary plant metabolites that appear to be effective in reducing levels of oxidative stress and inflammation in neural …

Gallium Nanoparticles Facilitate Phagosome Maturation And Inhibit Growth Of Virulent Mycobacterium Tuberculosis In Macrophages., Seoung-Ryoung Choi, Bradley E. Britigan, David M. Moran, Prabagaran Narayanasamy

Journal Articles: Pathology and Microbiology

New treatments and novel drugs are required to counter the growing problem of drug-resistant strains of Mycobacterium tuberculosis (M.tb). Our approach against drug resistant M.tb, as well as other intracellular pathogens, is by targeted drug delivery using nanoformulations of drugs already in use, as well as drugs in development. Among the latter are gallium (III) (Ga)-based compounds. In the current work, six different types of Ga and rifampin nanoparticles were prepared in such a way as to enhance targeting of M.tb infected-macrophages. They were then tested for their ability to inhibit growth of a fully pathogenic strain (H37Rv) or a …

Membrane-Active Epithelial Keratin 6a Fragments (Kamps) Are Unique Human Antimicrobial Peptides With A Non-Αβ Structure., Judy T.Y. Lee, Guangshun Wang, Yu Tong Tam, Connie Tam

Journal Articles: Pathology and Microbiology

Antibiotic resistance is a pressing global health problem that threatens millions of lives each year. Natural antimicrobial peptides and their synthetic derivatives, including peptoids and peptidomimetics, are promising candidates as novel antibiotics. Recently, the C-terminal glycine-rich fragments of human epithelial keratin 6A were found to have bactericidal and cytoprotective activities. Here, we used an improved 2-dimensional NMR method coupled with a new protocol for structural refinement by low temperature simulated annealing to characterize the solution structure of these kerain-derived antimicrobial peptides (KAMPs). Two specific KAMPs in complex with membrane mimicking sodium dodecyl sulfate (SDS) micelles displayed amphipathic conformations with only …

Il-10 Plays An Important Role In The Control Of Inflammation But Not In The Bacterial Burden In S. Epidermidis Cns Catheter Infection., Yenis M. Gutierrez-Murgas, Gwenn Skar, Danielle Ramirez, Matthew Beaver, Jessica N. Snowden

Journal Articles: Pathology and Microbiology

BACKGROUND: Shunt infection is a frequent and serious complication in the surgical treatment in hydrocephalus. Previous studies have shown an attenuated immune response to these biofilm-mediated infections. We proposed that IL-10 reduces the inflammatory response to Staphylococcus epidermidis (S. epidermidis) CNS catheter infection.

METHODS: In this study, a murine model of catheter-associated S. epidermidis biofilm infection in the CNS was generated based on a well-established similar model for S. aureus. The catheters were pre-coated with a clinically derived biofilm-forming strain of S. epidermidis (strain 1457) which were then stereotactically implanted into the lateral left ventricle of 8-week-old C57BL/6 and IL-10 …

Nox2-Derived Oxidative Stress Results In Inefficacy Of Antibiotics Against Post-Influenza S. Aureus Pneumonia., Keer Sun, Vijaya Kumar Yajjala, Christopher Bauer, G. Talmon, Karl J. Fischer, Tammy Kielian, Dennis W. Metzger

Journal Articles: Pathology and Microbiology

Clinical post-influenza Staphylococcus aureus pneumonia is characterized by extensive lung inflammation associated with severe morbidity and mortality even after appropriate antibiotic treatment. In this study, we show that antibiotics rescue nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (Nox2)-deficient mice but fail to fully protect WT animals from influenza and S. aureus coinfection. Further experiments indicate that the inefficacy of antibiotics against coinfection is attributable to oxidative stress-associated inflammatory lung injury. However, Nox2-induced lung damage during coinfection was not associated with aggravated inflammatory cytokine response or cell infiltration but rather caused by reduced survival of myeloid cells. Specifically, oxidative stress increased …

Recurrent Mutations Of T-Cell Receptor And Co-Stimulatory Signaling Proteins In Peripheral T-Cell Lymphomas, Joseph Rohr

Theses & Dissertations

Peripheral T-cell lymphomas (PTCLs) comprise a heterogeneous group of mature T-cell neoplasms with a poor prognosis. Recently, mutations in TET2 and other epigenetic modifiers as well as RHOA have been identified in these diseases, particularly in angioimmunoblastic T-cell lymphoma (AITL). CD28 is the major co-stimulatory receptor in T-cells which, upon binding ligand, induces sustained T-cell proliferation and cytokine production when combined with T-cell receptor stimulation, through many signaling molecules including VAV1. This thesis identifies recurrent mutations in CD28 in PTCLs, as well as mutations in VAV1. Two residues of CD28 – D124 and T195 – were recurrently mutated in 11.3% …

Moving Towards Effective Therapeutic Strategies For Neuronal Ceroid Lipofuscinosis., Ryan D. Geraets, Seung Yon Koh, Michelle L. Hastings, Tammy Kielian, David A. Pearce, Jill M. Weimer

Journal Articles: Pathology and Microbiology

The Neuronal Ceroid Lipofuscinoses (NCLs) are a family of autosomal recessive neurodegenerative disorders that annually affect 1:100,000 live births worldwide. This family of diseases results from mutations in one of 14 different genes that share common clinical and pathological etiologies. Clinically, the diseases are subcategorized into infantile, late-infantile, juvenile and adult forms based on their age of onset. Though the disease phenotypes may vary in their age and order of presentation, all typically include progressive visual deterioration and blindness, cognitive impairment, motor deficits and seizures. Pathological hallmarks of NCLs include the accumulation of storage material or ceroid in the lysosome, …

Neuroinflammatory Paradigms In Lysosomal Storage Diseases., Megan Bosch, Tammy Kielian

Journal Articles: Pathology and Microbiology

Lysosomal storage diseases (LSDs) include approximately 70 distinct disorders that collectively account for 14% of all inherited metabolic diseases. LSDs are caused by mutations in various enzymes/proteins that disrupt lysosomal function, which impairs macromolecule degradation following endosome-lysosome and phagosome-lysosome fusion and autophagy, ultimately disrupting cellular homeostasis. LSDs are pathologically typified by lysosomal inclusions composed of a heterogeneous mixture of various proteins and lipids that can be found throughout the body. However, in many cases the CNS is dramatically affected, which may result from heightened neuronal vulnerability based on their post-mitotic state. Besides intrinsic neuronal defects, another emerging factor common to …

Primary Sclerosing Epithelioid Fibrosarcoma Of Kidney With Variant Histomorphologic Features: Report Of 2 Cases And Review Of The Literature., Dilek Ertoy Baydar, Kemal Kosemehmetoglu, Oguz Aydin, Julia A. Bridge, Berrin Buyukeren, Fazil Tuncay Aki

Journal Articles: Pathology and Microbiology

The authors present two cases of primary sclerosing epithelioid fibrosarcoma (SEF) of the kidney. Both patients had a mass in the upper part of the left kidney without any primary extrarenal neoplastic lesions. Grossly, the tumors were solid masses both measuring 7.5 cm in the greatest diameter. Histologically, one of the lesions exhibited a predominantly lobular growth of round or oval small uniform epithelioid cells in variable cellularity. Circular zones of crowded tumor cells alternating with hypocellular collagenous tissue in a concentric fashion around entrapped native renal tubules were distinctive. The second case was distinctive with significant cytological atypia in …

Identifying The Critical Domain Of Ll-37 Involved In Mediating Neutrophil Activation In The Presence Of Influenza Virus: Functional And Structural Analysis., Shweta Tripathi, Guangshun Wang, Mitchell White, Michael Rynkiewicz, Barbara Seaton, Kevan Hartshorn

Journal Articles: Pathology and Microbiology

The human cathelicidin LL-37 has been shown to play a role in host defense against influenza A viruses (IAV) through direct antiviral effects and through modulating inflammatory responses to infection. We recently showed that LL-37 increases neutrophil respiratory burst and neutrophil extracellular trap (NET) responses to IAV through engaging formyl peptide receptor 2 (FPR-2). In this paper we show that a fragment of LL-37, GI-20, which is composed of the central helical segment of the peptide, has similar effects as LL-37 on neutrophil activation. In addition to increasing respiratory burst and NET responses of the cells to IAV through an …

Staphylococcus Aureus Biofilms Induce Macrophage Dysfunction Through Leukocidin Ab And Alpha-Toxin., Tyler D. Scherr, Mark L. Hanke, Ouwen Huang, David B.A. James, Alexander R. Horswill, Kenneth W. Bayles, Paul D. Fey, Victor J. Torres, Tammy Kielian

Journal Articles: Pathology and Microbiology

UNLABELLED: The macrophage response to planktonic Staphylococcus aureus involves the induction of proinflammatory microbicidal activity. However, S. aureus biofilms can interfere with these responses in part by polarizing macrophages toward an anti-inflammatory profibrotic phenotype. Here we demonstrate that conditioned medium from mature S. aureus biofilms inhibited macrophage phagocytosis and induced cytotoxicity, suggesting the involvement of a secreted factor(s). Iterative testing found the active factor(s) to be proteinaceous and partially agr-dependent. Quantitative mass spectrometry identified alpha-toxin (Hla) and leukocidin AB (LukAB) as critical molecules secreted by S. aureus biofilms that inhibit murine macrophage phagocytosis and promote cytotoxicity. A role for Hla …

Irreversible Dual Inhibitory Mode: The Novel Btk Inhibitor Pls-123 Demonstrates Promising Anti-Tumor Activity In Human B-Cell Lymphoma., Ning Ding, Xitao Li, Yunfei Shi, Lingyan Ping, Lina Wu, Kai Fu, Lixia Feng, Xiaohui Zheng, Yuqin Song, Zhengying Pan, Jun Zhu

Journal Articles: Pathology and Microbiology

The B-cell receptor (BCR) signaling pathway has gained significant attention as a therapeutic target in B-cell malignancies. Recently, several drugs that target the BCR signaling pathway, especially the Btk inhibitor ibrutinib, have demonstrated notable therapeutic effects in relapsed/refractory patients, which indicates that pharmacological inhibition of BCR pathway holds promise in B-cell lymphoma treatment. Here we present a novel covalent irreversible Btk inhibitor PLS-123 with more potent anti-proliferative activity compared with ibrutinib in multiple cellular and in vivo models through effective apoptosis induction and dual-action inhibitory mode of Btk activation. The phosphorylation of BCR downstream activating AKT/mTOR and MAPK signal pathways …

Loss Of Cbl And Cbl-B Ubiquitin Ligases Abrogates Hematopoietic Stem Cell Quiescence And Sensitizes Leukemic Disease To Chemotherapy., Wei An, Scott A. Nadeau, Bhopal C. Mohapatra, Dan Feng, Neha Zutshi, Matthew D. Storck, Priyanka Arya, James E. Talmadge, Jane L. Meza, Vimla Band, Hamid Band

Journal Articles: Pathology and Microbiology

Cbl and Cbl-b are tyrosine kinase-directed RING finger type ubiquitin ligases (E3s) that negatively regulate cellular activation pathways. E3 activity-disrupting human Cbl mutations are associated with myeloproliferative disorders (MPD) that are reproduced in mice with Cbl RING finger mutant knock-in or hematopoietic Cbl and Cbl-b double knockout. However, the role of Cbl proteins in hematopoietic stem cell (HSC) homeostasis, especially in the context of MPD is unclear. Here we demonstrate that HSC expansion and MPD development upon combined Cbl and Cbl-b deletion are dependent on HSCs. Cell cycle analysis demonstrated that DKO HSCs exhibit reduced quiescence associated with compromised reconstitution …

Antiviral Activity Of The Human Cathelicidin, Ll-37, And Derived Peptides On Seasonal And Pandemic Influenza A Viruses., Shweta Tripathi, Guangshun Wang, Mitchell White, Li Qi, Jeffery Taubenberger, Kevan L. Hartshorn

Journal Articles: Pathology and Microbiology

Human LL-37, a cationic antimicrobial peptide, was recently shown to have antiviral activity against influenza A virus (IAV) strains in vitro and in vivo. In this study we compared the anti-influenza activity of LL-37 with that of several fragments derived from LL-37. We first tested the peptides against a seasonal H3N2 strain and the mouse adapted H1N1 strain, PR-8. The N-terminal fragment, LL-23, had slight neutralizing activity against these strains. In LL-23V9 serine 9 is substituted by valine creating a continuous hydrophobic surface. LL-23V9 has been shown to have increased anti-bacterial activity compared to LL-23 and we now show slightly …

Antimicrobial Peptides In 2014., Guangshun Wang, Biswajit Mishra, Kyle Lau, Tamara Lushnikova, Radha Golla, Xiuqing Wang

Journal Articles: Pathology and Microbiology

This article highlights new members, novel mechanisms of action, new functions, and interesting applications of antimicrobial peptides reported in 2014. As of December 2014, over 100 new peptides were registered into the Antimicrobial Peptide Database, increasing the total number of entries to 2493. Unique antimicrobial peptides have been identified from marine bacteria, fungi, and plants. Environmental conditions clearly influence peptide activity or function. Human α-defensin HD-6 is only antimicrobial under reduced conditions. The pH-dependent oligomerization of human cathelicidin LL-37 is linked to double-stranded RNA delivery to endosomes, where the acidic pH triggers the dissociation of the peptide aggregate to release …