374 research outputs found
Thrombospondin-1: Multiple Paths to Inflammation
Inflammation is a defensive process against tissue injury. Once this self-protective strategy is initiated, an effective resolution of the process is crucial to avoid major and unnecessary tissue damage. If the underlying event inducing inflammation is not addressed and homeostasis is not restored, this process can become chronic and lead to angiogenesis and carcinogenesis. Thrombospondin-1 (TSP-1) is a matricellular protein involved in angiogenesis, cancer, and inflammation. The effects of TSP-1 have been studied in many preclinical tumor models, and mimetic peptides are being tested in cancer clinical trials. However, the molecular mechanisms explaining its role in inflammatory processes are not well understood. This paper will discuss the role of TSP-1 in inflammation and its interaction with key receptors that may explain its functions in that process. Recent literature will be reviewed showing novel mechanisms by which this multifaceted protein could modulate the inflammatory process and impact its resolution
Thrombospondin-1 Type 1 Repeats in a Model of Inflammatory Bowel Disease: Transcript Profile and Therapeutic Effects
Thrombospondin-1 (TSP-1) is a matricellular protein with regulatory functions in inflammation and cancer. The type 1 repeats (TSR) domains of TSP-1 have been shown to interact with a wide range of proteins that result in the anti-angiogenic and anti-tumor properties of TSP-1. To ascertain possible functions and evaluate potential therapeutic effects of TSRs in inflammatory bowel disease, we conducted clinical, histological and microarray analyses on a mouse model of induced colitis. We used dextran sulfate sodium (DSS) to induce colitis in wild-type (WT) mice for 7 days. Simultaneously, mice were injected with either saline or one form of TSP-1 derived recombinant proteins, containing either (1) the three type 1 repeats of the TSP-1 (3TSR), (2) the second type 1 repeat (TSR2), or (3) TSR2 with the RFK sequence (TSR2+RFK). Total RNA isolated from the mice colons were processed and hybridized to mouse arrays. Array data were validated by real-time qPCR and immunohistochemistry. Histological and disease indices reveal that the mice treated with the TSRs show different patterns of leukocytic infiltration and that 3TSR treatment was the most effective in decreasing inflammation in DSS-induced colitis. Transcriptional profiling revealed differentially expressed (DE) genes, with the 3TSR-treated mice showing the least deviation from the WT-water controls. In conclusion, this study shows that 3TSR treatment is effective in attenuating the inflammatory response to DSS injury. In addition, the transcriptomics work unveils novel genetic data that suggest beneficial application of the TSR domains in inflammatory bowel disease
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Thrombospondin-1 in a Murine Model of Colorectal Carcinogenesis
Colorectal Cancer (CRC) is one of the late complications observed in patients suffering from inflammatory bowel diseases (IBD). Carcinogenesis is promoted by persistent chronic inflammation occurring in IBD. Understanding the mechanisms involved is essential in order to ameliorate inflammation and prevent CRC. Thrombospondin 1 (TSP-1) is a multidomain glycoprotein with important roles in angiogenesis. The effects of TSP-1 in colonic tumor formation and growth were analyzed in a model of inflammation-induced carcinogenesis. WT and TSP-1 deficient mice (TSP-1-/-) of the C57BL/6 strain received a single injection of azoxymethane (AOM) and multiple cycles of dextran sodium sulfate (DSS) to induce chronic inflammation-related cancers. Proliferation and angiogenesis were histologically analyzed in tumors. The intestinal transcriptome was also analyzed using a gene microarray approach. When the area containing tumors was compared with the entire colonic area of each mouse, the tumor burden was decreased in AOM/DSS-treated TSP-1-/- versus wild type (WT) mice. However, these lesions displayed more angiogenesis and proliferation rates when compared with the WT tumors. AOM-DSS treatment of TSP-1-/- mice resulted in significant deregulation of genes involved in transcription, canonical Wnt signaling, transport, defense response, regulation of epithelial cell proliferation and metabolism. Microarray analyses of these tumors showed down-regulation of 18 microRNAs in TSP-1-/- tumors. These results contribute new insights on the controversial role of TSP-1 in cancer and offer a better understanding of the genetics and pathogenesis of CRC
PenQuest Volume 1, Number 2
Table of Contents for this Volume:
Untitled by Julie Ambrose
Night by Judith Gallo
Untitled by Judy Gozdur
the shamans by Charles Riddles
Untitled by Jerry Connell
Untitled by Laura Woods
Untitled by LEMA
Wicked Bird by Laura Jo Last
Untitled by Rick Dentos
Untitled by Jeni Moody
Untitled by Bettie W. Kwibs
Untitled by Joann Stagg
The Protector Stood by Laura Jo Last
Visions of Salome by Charles Riddles
Untitled by Thomas Tutten
Kennesaw Line by Don Ova-Dunaway
Stone Blood by Mary Ellen C. Wofford
Untitled by Roger Whitt Jr.
Untitled by C. Wingate
Untitled by Doug Dorey
Untitled by Karen Blumberg
Untitled by Beverly Oviatt
Untitled by Virginia Shrader
The Crapulous Credo of Charles C. by Charles Riddles
the brave and the true by David Reed
Untitled by Charles Gutierrez
Canoe Creek by Patricia Kraft
Untitled by Linda Bobinger
The Man in the Iron Lung by Patricia Kraft
Untitled by Roger Whitt, Jr.
Childish Things by Kathleen Gay
Untitled by Joseph Avanzini
The Lover by Mary S. Aken
Untitled by Ann Harrington
And He Taketh Away by David Reed
Untitled by Mary Graham
Untitled by Melody A. Cummons
Untitled by Karen Blumberg
To The Poets by Judith Gallo
Untitled by Ann Harringto
Prevalence of Dementia and Mild Cognitive Impairment in Indigenous Bolivian Forager-Horticulturalists
Introduction
We evaluated the prevalence of dementia and mild cognitive impairment (MCI) in indigenous Tsimane and Moseten, who lead a subsistence lifestyle. Methods
Participants from population-based samples ≥ 60 years of age (n = 623) were assessed using adapted versions of the Modified Mini-Mental State Examination, informant interview, longitudinal cognitive testing and brain computed tomography (CT) scans. Results
Tsimane exhibited five cases of dementia (among n = 435; crude prevalence = 1.2%, 95% confidence interval [CI]: 0.4, 2.7); Moseten exhibited one case (among n = 169; crude prevalence = 0.6%, 95% CI: 0.0, 3.2), all age ≥ 80 years. Age-standardized MCI prevalence was 7.7% (95% CI: 5.2, 10.3) in Tsimane and 9.8% (95% CI: 4.9, 14.6) in Moseten. Cognitive impairment was associated with visuospatial impairments, parkinsonian symptoms, and vascular calcification in the basal ganglia. Discussion
The prevalence of dementia in this cohort is among the lowest in the world. Widespread intracranial medial arterial calcifications suggest a previously unrecognized, non-Alzheimer\u27s disease (AD) dementia phenotype
17β-estradiol promotes extracellular vesicle release and selective miRNA loading in ERα-positive breast cancer
The causes and consequences of abnormal biogenesis of extracellular vesicles (EVs) are not yet well understood in malignancies, including in breast cancers (BCs). Given the hormonal signaling dependence of estrogen receptor–positive (ER+) BC, we hypothesized that 17β-estradiol (estrogen) might influence EV production and microRNA (miRNA) loading. We report that physiological doses of 17β-estradiol promote EV secretion specifically from ER+ BC cells via inhibition of miR-149-5p, hindering its regulatory activity on SP1, a transcription factor that regulates the EV biogenesis factor nSMase2. Additionally, miR-149-5p downregulation promotes hnRNPA1 expression, responsible for the loading of let-7’s miRNAs into EVs. In multiple patient cohorts, we observed increased levels of let-7a-5p and let-7d-5p in EVs derived from the blood of premenopausal ER+ BC patients, and elevated EV levels in patients with high BMI, both conditions associated with higher levels of 17β-estradiol. In brief, we identified a unique estrogen-driven mechanism by which ER+ BC cells eliminate tumor suppressor miRNAs in EVs, with effects on modulating tumor-associated macrophages in the microenvironment
Mammalian Target of Rapamycin (mTOR) Activity Dependent Phospho-Protein Expression in Childhood Acute Lymphoblastic Leukemia (ALL)
Modern treatment strategies have improved the prognosis of childhood ALL; however, treatment still fails in 25–30% of
patients. Further improvement of treatment may depend on the development of targeted therapies. mTOR kinase, a central
mediator of several signaling pathways, has recently attracted remarkable attention as a potential target in pediatric ALL.
However, limited data exists about the activity of mTOR. In the present study, the amount of mTOR activity dependent
phospho-proteins was characterized by ELISA in human leukemia cell lines and in lymphoblasts from childhood ALL
patients (n = 49). Expression was measured before and during chemotherapy and at relapses. Leukemia cell lines exhibited
increased mTOR activity, indicated by phospho-S6 ribosomal protein (p-S6) and phosphorylated eukaryotic initiation factor
4E binding protein (p-4EBP1). Elevated p-4EBP1 protein levels were detected in ALL samples at diagnosis; efficacy of
chemotherapy was followed by the decrease of mTOR activity dependent protein phosphorylation. Optical density (OD) for
p-4EBP1 (ELISA) was significantly higher in patients with poor prognosis at diagnosis, and in the samples of relapsed
patients. Our results suggest that measuring mTOR activity related phospho-proteins such as p-4EBP1 by ELISA may help to
identify patients with poor prognosis before treatment, and to detect early relapses. Determining mTOR activity in leukemic
cells may also be a useful tool for selecting patients who may benefit from future mTOR inhibitor treatments
Models of Traumatic Cerebellar Injury
Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide. Studies of human TBI demonstrate that the cerebellum is sometimes affected even when the initial mechanical insult is directed to the cerebral cortex. Some of the components of TBI, including ataxia, postural instability, tremor, impairments in balance and fine motor skills, and even cognitive deficits, may be attributed in part to cerebellar damage. Animal models of TBI have begun to explore the vulnerability of the cerebellum. In this paper, we review the clinical presentation, pathogenesis, and putative mechanisms underlying cerebellar damage with an emphasis on experimental models that have been used to further elucidate this poorly understood but important aspect of TBI. Animal models of indirect (supratentorial) trauma to the cerebellum, including fluid percussion, controlled cortical impact, weight drop impact acceleration, and rotational acceleration injuries, are considered. In addition, we describe models that produce direct trauma to the cerebellum as well as those that reproduce specific components of TBI including axotomy, stab injury, in vitro stretch injury, and excitotoxicity. Overall, these models reveal robust characteristics of cerebellar damage including regionally specific Purkinje cell injury or loss, activation of glia in a distinct spatial pattern, and traumatic axonal injury. Further research is needed to better understand the mechanisms underlying the pathogenesis of cerebellar trauma, and the experimental models discussed here offer an important first step toward achieving that objective
Intelligent feature selection and classification techniques for intrusion detection in networks: a survey
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