Vascular endothelial growth factor (VEGF) is a potent cell mitogen involved in normal and abnormal angiogenesis. VEGF mRNA protein are abundant distal epithelium of midtrimester human fetal lung. In the present study, we identified immunoreactivity for KDR, major VEGF-specific receptor, lung epithelial cells tissue, suggesting possible autocrine or paracrine regulatory role pulmonary differentiation. Addition exogenous to explants resulted increased volume density lumen tissues, both...

Inhibition of ribonucleotide reductase (RNR), the rate-limiting enzyme in synthesis deoxyribonucleotides, causes DNA replication stress and activates ataxia telangiectasia rad3-related protein (ATR)-checkpoint kinase 1 (CHK1) pathway. Notably, a number different cancers, including Ewing sarcoma tumors, are sensitive to combination RNR ATR-CHK1 inhibitors. However, multiple, overlapping mechanisms reported underlie toxicity inhibitors, both as single agents with toward cancer cells. Here, we...

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There is a critical need in cancer therapeutics to identify targeted therapies that will improve outcomes and decrease toxicities compared conventional, cytotoxic chemotherapy. Ewing sarcoma highly aggressive bone soft tissue caused by the EWS-FLI1 fusion protein. Although specific for cells, required tumorigenesis, directly targeting this transcription factor has proven challenging. Consequently, unique dependencies or key downstream mediators of represent important alternative strategies....

The treatment of Ewing sarcoma has changed very little in the past two decades and novel approaches are needed. We recently identified that cells uniquely vulnerable to inhibitors ribonucleotide reductase (RNR), rate-limiting enzyme synthesis deoxyribonucleotides. subsequently found inhibition checkpoint kinase 1 (CHK1) increases sensitivity RNR, such as gemcitabine. However, exhibit high levels CHK1 protein, which may represent an adaptive response elevated endogenous DNA replication...

Surfactant protein D (SP-D) is a lung collectin involved in innate host defence mechanisms the lung. SP-D also expressed at other mucosal sites throughout human body. In present study, we show that mRNA and are female reproductive tract. was localized apical portion of epithelial cells. We demonstrate endometrial endocervical cell lines primary cells culture produce protein. Chlamydia trachomatis an intracellular pathogen infects tract, primarily cervix, responsible for most prevalent...

The systemic inflammatory response syndrome (SIRS) is a clinical condition occurring in intensive care unit patients as consequence of both infectious and noninfectious insults. mechanisms underlying resolution SIRS are not well characterized. NOX2 (NADPH oxidase 2)-derived reactive oxygen species critical for killing certain pathogens by polymorphonuclear leukocytes (PMN). Patients with chronic granulomatous disease who lack functional only prone to serious infections, they also exhibit...

// Kelli L. Goss 1 , Stacia Koppenhafer Kathryn M. Harmoney William W. Terry and David J. Gordon Department of Pediatrics, Division Pediatric Hematology/Oncology, University Iowa, Iowa City, 52242, USA Correspondence to: Gordon, email: david-j-gordon@uiowa.edu Keywords: Ewing sarcoma, ribonucleotide reductase, gemcitabine, CHK1, replication stress Received: March 06, 2017 Accepted: May 22, Published: June 28, ABSTRACT sarcoma is a bone soft tissue that occurs in children young adults. The...

Activation of polymorphonuclear leukocytes (PMN) can be modulated to intermediate ‘primed’ states characterized by enhanced responsiveness subsequent stimuli. We studied priming in response TNF-α human PMN and PLB-985 cells, a myeloid cell line differentiated neutrophilic phenotype (PLB-D). generated reactive oxygen species (ROS) alone, NADPH oxidase activity increased stimulation with formyl-Met-Leu-Phe after priming. PLB-D cells also demonstrated activity. Similar endotoxin, the...

It has been proposed that high insulin levels may cause delayed lung development in the fetuses of diabetic mothers. A key event is production adequate amounts pulmonary surfactant. Insulin inhibits expression surfactant protein (SP-A), major surfactant-associated protein, epithelial cells. In present study, we investigated signal transduction pathways involved inhibition SP-A gene expression. H441 cells, a human adenocarcinoma cell line, or fetal explants were incubated with without...

Surfactant protein D (SP-D) is a constituent of the innate immune system that plays role in host defense against lung pathogens and modulating inflammatory responses. While SP-D has been detected extrapulmonary tissues, little known about its expression function vasculature. Immunostaining human coronary artery tissue sections demonstrated immunoreactive smooth muscle cells (SMCs) endothelial cells. was also isolated SMCs (HCASMCs) by PCR immunoblot analysis. Treatment HCASMCs with endotoxin...

In the present study, pulmonary surfactant protein A (SP-A) messenger RNA (mRNA) and were characterized in adult rabbit middle ear maxillary sinus. Fifteen rabbits used for study: 6 with evidence of acute infections sinusitis, that successfully treated tetracycline, 3 pathogen-free. We detected SP-A mRNA sinus tissues by Northern blot analysis reverse transcriptase—polymerase chain reaction (RT-PCR). The RT-PCR also revealed presence SP-B SP-C tissues. protein, molecular weight approximately...

Human conducting airways contain two anatomically distinct epithelial cell compartments: surface epithelium and submucosal glands (SMG). Surface cells interface directly with the environment function in pathogen detection, fluid electrolyte transport, mucus elevation. SMG secrete antimicrobial molecules most of airway fluid. Despite unique functional roles epithelia SMG, little is known about differences gene expression cellular metabolism that orchestrate specialized functions these...

Systemic inflammatory response syndrome (SIRS) is a common clinical condition in patients intensive care units that can lead to complications, including multiple organ dysfunction (MODS). MODS carries high mortality rate, and it unclear why some resolve SIRS, whereas others develop MODS. Although oxidant stress has been implicated the development of MODS, several recent studies have demonstrated requirement for NADPH oxidase 2 (NOX2)-derived oxidants limiting inflammation. We recently NOX2...

Abstract OBJECTIVES Surfactant protein D (SP‐D) is a member of the collectin family proteins, which are involved in host defense mechanisms lung. In present study, we found that SP‐D produced human prostate where it may play role innate immunity. METHODS AND RESULTS Using reverse‐transcriptase PCR and Western blot analysis, demonstrate mRNA tissue. situ hybridization immunohistochemistry revealed localized epithelial cells glands. Prostate glands surrounded by inflammatory produce increased...

The collectins surfactant-associated protein A (SP-A) and SP-D are components of innate immunity that present before birth. Both proteins bind pathogens assist in clearing infection. significance SP-A as the neonatal immune system has not been investigated. To determine role immunity, wild-type, null, null mice were bred a bacterium-laden environment (corn dust bedding) or semisterile (cellulose fiber bedding). When reared corn bedding, pups had significant mortality (P < 0.001) compared to...

The surfactant proteins (SPs) are required for the normal function of pulmonary surfactant, a lipoprotein substance that prevents alveolar collapse at end expiration. We characterized effects cortisol and all trans-retinoic acid (RA) on SP-A SP-B gene expression in H441 cells, human adenocarcinoma cell line. Cortisol, 10 −6 M, caused significant inhibition mRNA to levels were 60–70% controls five- sixfold increase mRNA. RA alone (10 M) had no effect modestly reduced inhibitory cortisol....

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In mice, alveolarization occurs during postnatal days 4 through 12, when secondary alveolar septae create thin-walled alveoli in the distal lung. We hypothesized that genes predominantly expressed newly forming influence process of alveolarization. To address this hypothesis, tips were isolated from sections day 6 mouse lung tissue using laser capture microdissection. Total RNA was and amplified dissected septal intact tissue. Gene expression samples characterized Affymetrix U74AN2...

Surfactant protein D (SP-D) plays a role in innate immunity the lung and is expressed at many other mucosal surfaces throughout human body. In this study, we show that SP-D mRNA are present murine female reproductive tract; i.e. vagina, cervix, uterus oviduct. primarily localized to epithelial cells lining genital tract also secretory material within lumen of cervix. The levels vary by factor 10 during estrous cycle with peak estrus lowest diestrus. contrast, do not change cycle. Since an...

Ribonucleotide reductase (RNR) catalyzes the rate-limiting step in synthesis of deoxyribonucleosides and is required for DNA replication. Multiple types cancer, including Ewing sarcoma tumors, are sensitive to RNR inhibitors or a reduction levels either RRM1 RRM2 subunits RNR. However, polypharmacology off-target effects have complicated identification mechanisms that regulate sensitivity resistance this class drugs. Consequently, we used conditional knockout (CRISPR/Cas9) rescue approach...

Surfactant protein D (SP-D) is an innate immune that present in mucosal lined surfaces throughout the human body, including male reproductive tract. In study, we characterized regulation of SP-D expression mouse and rat prostate.Real time reverse transcriptase polymerase chain reaction (RT-PCR) immunostaining were used to characterize mRNA order evaluate effects testosterone on gene expression, measured levels via real RT-PCR prostates from sham-castrated mice castrated mice. addition, a...

Abstract Background The treatment of Ewing sarcoma, an aggressive bone and soft tissue is associated with suboptimal outcomes significant side-effects. Consequently, there urgent need to identify novel therapies that will improve for children adults sarcoma tumors while also decreasing treatment-related toxicities. Methods We analyzed data from the PRISM drug repurposing screen, which tested activity 4518 drugs across 578 cancer cell lines, selectively inhibit growth lines. then effects a...