tbuckley/cabot-search huggingface dataset:
miR-155 and miR-34a regulate proinflammatory cytokine production by human monocytes
Authors: M Kurowska-Stolarska, L Ballantine, B Stolarski, J Hunter, A Hueber, J A Gracie, F Y Liew, I B McInnes
Journal: Annals of the Rheumatic Diseases (2010)

Purpose Dysregulated proinfl ammatory activation of synovial monocytes and macrophages is of fundamental importance in the pathogenesis of rheumatoid arthritis (RA).Recently, microRNAs (miRNA) have been identifi ed as critical posttranscriptional regulators of many components of immune responses.The aim of our study was to investigate the role of candidate miRNAs miR-155 and miR-34a in the activation of RA synovial fl uid (SF) and blood monocyte/macrophages. Methods CD14 cells from SF or blood of RA patients and CD14 cells from blood of healthy controls were isolated using CD14 MACS MicroBeads.Peripheral blood (PB) CD14 cells were stimulated with lipopolysaccharide (100 ng/ml), Pam3CSK4 (300 ng/ml), PolyI:C (50 μg/ml), CPG (3 μg/ml) or control CPG (3 μg/ml).PB CD14 cells were transfected with miR-155, miR-34a and scramble mimics (all 3.5 µg/3×10 6 cells) by electroporation.Total RNA was isolated by miRNeasy kit.TaqMan miRNA and mRNA assays were used for semi-quantitative determination of the expression of miR-155, miR-34a and AXL, respectively.The expressions of U6B small nuclear RNA and ribosomal 18S or β-actin were used as endogenous controls.To identify the cellular targets of candidate miRs, multiple target prediction programmes and mRNA transcriptomic signatures of SF CD14 cells were employed.Results SF CD14 cells expressed higher levels of miR-155 (64-fold, p<0.05) and miR-34a (4.5-fold, p<0.05) than blood matched CD14 cells.Expression of miR-155 was upregulated by TLR2, TLR3, TLR4 and TLR9 ligands (p<0.05) in PB CD14 cells.In contrast, miR-34a expression was either not affected (Pam3CSK4) or downregulated (LPS, PolyI:C, CPG; p<0.05) under the same conditions.Overexpression of miR-155 and miR-34a mimics in blood monocytes induced tumour necrosis factor α (TNFα) production (10170±385 pg/ml) and (991±33 pg/ ml), respectively.In addition, overexpression of miR-155 but not miR-34a in human PB monocytes increased interleukin 6 (IL-6) production.Using computational target ranking system combined with mRNA transcriptomic data, the authors identifi ed a negative regulator of TLR/IL-1R signalling, AXL (tyrosine kinase receptor) to be targeted by both miRs.Overexpression of miR-34a and miR-155 mimics decreased the expression of AXL in blood monocytes by 48±3% and 38±16%, respectively.Conclusion These data suggest that overexpression of miR-155 and miR-34a in CD14 cells can result in downregulation of AXL expression which in turn can lead to the overproduction of TNFα.The authors provide a novel mechanism for deregulated TNF production in RA synovial macrophages amenable to therapeutic intervention in due course.
C3a is a chemotaxin for human eosinophils but not for neutrophils. I. C3a stimulation of neutrophils is secondary to eosinophil activation.
Authors: P J Daffern, P H Pfeifer, J A Ember, T E Hugli
Journal: The Journal of Experimental Medicine (1995)

Inflammatory action of the potent chemotaxin C5a has been well characterized on a variety of human cell types, including neutrophils, monocytes, basophils, and eosinophils. The cellular effects of C3a are less well defined. Contradictory reports have been published for C3a activation of neutrophils. Recent reports that C3a activates both basophils and eosinophils prompted us to reinvestigate the effects of C3a stimulation on eosinophils. We hypothesized that C3a activation of eosinophils, cells that are present in most neutrophil preparations, might lead to neutrophil activation. Using neutrophils of 98% purity, we observed no evidence of cellular activation after stimulation with either C3a, recombinant human C3a (rhC3a), or the synthetic C3a analogue C3a 57-77, Y57. Eosinophils purified to &amp;gt; 98% purity displayed concentration-dependent polarization, chemotaxis, and enzyme release by stimulation with C3a, rhC3a, and the synthetic C3a analogue. An inactive form of C3a, C3adesArg, failed to stimulate either eosinophils or neutrophils. Using neutrophil preparations containing 5-9% eosinophils, up to 20% of neutrophils became polarized after exposure to C3a. Likewise, we demonstrated that supernatant from C3a-stimulated eosinophils promotes neutrophil chemotaxis. Eosinophil polarization experiments were repeated in the presence of antibody to the C5a receptor (C5aR) to show that C3a and C5a interact with different receptors. C3a activates eosinophils in the presence of anti-C5aR antibody at concentrations that fully block C5a activation. We conclude that eosinophils are directly activated by either C3a or C5a, whereas C3a failed to activate neutrophils. C3a acts on eosinophils via a receptor that is distinct from C5aR. Since neutrophils are indirectly stimulated by C3a, eosinophils contaminating neutrophil preparations may explain earlier reports that C3a activates human neutrophils.
Evaluation of Nasal Patency and Nasal Nitric Oxide Levels in Subjects with Allergic Rhinitis After Pharmacologic or Physiologic Stimuli: a Two Parallel Groups Study
Authors: C.D. Serrano, A.L. Valero, J. Bartra, A. Torrego, J. Mullol, C. Picado
Journal: Journal of Allergy and Clinical Immunology (2006)
The Treatment of Stages I–IV Favorable Histology Wilms' Tumor
Authors: Daniel M. Green
Journal: Journal of Clinical Oncology (2004)

From central pathology review; regimen as assigned by Data and Statistical Center.Numeral after K or DD indicates RT dose (Gy), Ϭ 10. †A few randomly assigned children were not assessed for outcome because they lacked follow-up of any kind.‡Relapses and (toxic) deaths counted as failures.§Number expected assuming no difference between regimens.Estimated based on Kaplan-Meier curves.¶95% CI based on log-rank transformation in Kaplan-Meier survival analysis.#Stratified by the two/ strata of FH III K1 and DD1 and FH III K2 and DD2.‫ءء‬ Stratified by the two/ strata of FH III DD1 and DD2 and FH III K1 and K2.† †Stratified by the four strata of FH II DD and K, FH II DD2 and K2, FH III DD1 and K1 and FH III DD2 and K2.
Dose Escalation of Lenalidomide in Relapsed or Refractory Acute Leukemias
Authors: William Blum, Rebecca B. Klisovic, Heiko Becker, Xiaoxia Yang, Darlene M. Rozewski, Mitch A. Phelps, Ramiro Garzon, Alison Walker, Jason C. Chandler, Susan P. Whitman, John Curfman, Shujun Liu, Larry Schaaf, Jon Mickle, Cheryl Kefauver, Steven M. Devine, Michael R. Grever, Guido Marcucci, and, John C. Byrd
Journal: Journal of Clinical Oncology (2010)

Purpose Lenalidomide is effective in myeloma and low-risk myelodysplastic syndromes with deletion 5q. We report results of a phase I dose-escalation trial of lenalidomide in relapsed or refractory acute leukemia. Patients and Methods Thirty-one adults with acute myeloid leukemia (AML) and four adults with acute lymphoblastic leukemia (ALL) were enrolled. Lenalidomide was given orally at escalating doses of 25 to 75 mg daily on days 1 through 21 of 28-day cycles to determine the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD), as well as to provide pharmacokinetic and preliminary efficacy data. Results Patients had a median age of 63 years (range, 22 to 79 years) and a median of two prior therapies (range, one to four therapies). The DLT was fatigue; 50 mg/d was the MTD. Infectious complications were frequent. Plasma lenalidomide concentration increased proportionally with dose. In AML, five (16%) of 31 patients achieved complete remission (CR); three of three patients with cytogenetic abnormalities achieved cytogenetic CR (none with deletion 5q). Response duration ranged from 5.6 to 14 months. All responses occurred in AML with low presenting WBC count. No patient with ALL responded. Two of four patients who received lenalidomide as initial therapy for AML relapse after allogeneic transplantation achieved durable CR after development of cutaneous graft-versus-host disease, without donor leukocyte infusion. Conclusion Lenalidomide was safely escalated to 50 mg daily for 21 days, every 4 weeks, and was active with relatively low toxicity in patients with relapsed/refractory AML. Remissions achieved after transplantation suggest a possible immunomodulatory effect of lenalidomide, and results provide enthusiasm for further studies in AML, either alone or in combination with conventional agents or other immunotherapies.
Estrogen Receptor β Inhibits Human Breast Cancer Cell Proliferation and Tumor Formation by Causing a G2 Cell Cycle Arrest
Authors: Sreenivasan Paruthiyil, Hema Parmar, Vaishali Kerekatte, Gerald R. Cunha, Gary L. Firestone, Dale C. Leitman
Journal: Cancer Research (2004)

Studies indicate that estrogen receptor (ER) alpha mediates breast cancer-promoting effects of estrogens. The role of ERbeta in breast cancer is unknown. Elucidating the role of ERbeta in the pathogenesis of breast cancer is important because many human breast tumors express both ERalpha and ERbeta. We show that adenovirus-mediated expression of ERbeta changes the phenotype of ERalpha-positive MCF-7 cells. Estradiol increases cell proliferation and causes tumor formation of MCF-7 cells expressing only ERalpha. In contrast, introducing ERbeta into MCF-7 cells causes an inhibition of proliferation in vitro and prevents tumor formation in a mouse xenograft model in response to estradiol. ERbeta inhibits proliferation by repressing c-myc, cyclin D1, and cyclin A gene transcription, and increasing the expression of p21(Cip1) and p27(Kip1), which leads to a G(2) cell cycle arrest. These results demonstrate that ERalpha and ERbeta produce opposite effects in MCF-7 cells on cell proliferation and tumor formation. Natural or synthetic ERbeta-selective estrogens may lack breast cancer promoting properties exhibited by estrogens in hormone replacement regimens and may be useful for chemoprevention of breast cancer.
Role of 15-hydroxyprostaglandin dehydrogenase down-regulation on the prognosis of hepatocellular carcinoma
Authors: Jee Eun Yang, Eunji Park, Hyo Jeong Lee, Hyo Jeong Kang, Kang Mo Kim, Eunsil Yu, Danbi Lee, Ju Hyun Shim, Young-Suk Lim, Han Chu Lee, Young-Hwa Chung, Yung Sang Lee
Journal: Clinical and Molecular Hepatology (2014)

Background/Aims The role of prostaglandin E2 (PGE2) in the modulation of cell growth is well established in colorectal cancer. The aim of this study was to elucidate the significance of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) down-regulation on the prognosis of hepatocellular carcinoma (HCC) patients. Methods The expression of 15-PGDH in HCC cell lines and resected HCC tissues was investigated, and the correlation between 15-PGDH expression and HCC cell-line proliferation and patient survival was explored. Results The interleukin-1-Î²-induced suppression of 15-PGDH did not change the proliferation of PLC and Huh-7 cells in the MTS [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. The induction of 15-PGDH by transfection in HepG2 cells without baseline 15-PGDH expression was suppressed at day 2 of proliferation compared with empty-vector transfection, but there was no difference at day 3. Among the 153 patients who received curative HCC resection between 2003 and 2004 at our institution, 15-PGDH expression was observed in resected HCC tissues in 56 (36.6%), but the 5-year survival rate did not differ from that of the remaining 97 non-15-PGDH-expressing patients (57.1% vs 59.8%; P=0.93). Among 50 patients who exhibited baseline 15-PGDH expression in adjacent nontumor liver tissues, 28 (56%) exhibited a reduction in 15-PGDH expression score in HCC tissues, and there was a trend toward fewer long-term survivors compared with the remaining 22 with the same or increment in their 15-PGDH expression score in HCC tissues. Conclusions The prognostic significance of 15-PGDH down-regulation in HCC was not established in this study. However, maintenance of 15-PGDH expression could be a potential therapeutic target for a subgroup of HCC patients with baseline 15-PGDH expression in adjacent nontumor liver tissue. Keywords: Hepatocellular carcinoma; 15-hydroxyprostaglandin dehydrogenase; Transfection; Immunohistochemistry; Survival analysis
The Glomerular Injury of Preeclampsia
Authors: Isaac E. Stillman, S. Ananth Karumanchi
Journal: Journal of the American Society of Nephrology (2007)

Preeclampsia is a pregnancy-specific disorder that complicates approximately 5% of all pregnancies, making it perhaps the most common glomerular disease in the world. It is characterized by new-onset hypertension and proteinuria, in association with a characteristic glomerular lesion, endotheliosis. "Glomerular endotheliosis" represents a specific variant of thrombotic microangiopathy that is characterized by glomerular endothelial swelling with loss of endothelial fenestrae and occlusion of the capillary lumens. Associated thrombosis is unusual. Recent evidence suggests that this unusual glomerular lesion is mediated by a soluble vascular endothelial growth factor receptor that deprives glomerular endothelial cells of the vascular endothelial growth factor that they require, leading to cellular injury and disruption of the filtration apparatus with subsequent proteinuria. This review summarizes the histologic changes and the pathogenesis of the glomerular lesions of preeclampsia.
Involvement of gut microbiota in the development of low-grade inflammation and type 2 diabetes associated with obesity
Authors: Patrice D. Cani, Melania Osto, Lucie Geurts, Amandine Everard
Journal: Gut Microbes (2012)

Obesity is associated with metabolic alterations related to glucose homeostasis and cardiovascular risk factors. These metabolic alterations are associated with low-grade inflammation that contributes to the onset of these diseases. We and others have provided evidence that gut microbiota participates in whole-body metabolism by affecting energy balance, glucose metabolism, and low-grade inflammation associated with obesity and related metabolic disorders. Recently, we defined gut microbiota-derived lipopolysaccharide (LPS) (and metabolic endotoxemia) as a factor involved in the onset and progression of inflammation and metabolic diseases. In this review, we discuss mechanisms involved in the development of metabolic endotoxemia such as the gut permeability. We also discuss our latest discoveries demonstrating a link between the gut microbiota, endocannabinoid system tone, leptin resistance, gut peptides (glucagon-like peptide-1 and -2), and metabolic features. Finally, we will introduce the role of the gut microbiota in specific dietary treatments (prebiotics and probiotics) and surgical interventions (gastric bypass).
Rainbow pattern in Kaposi’s sarcoma under polarized dermoscopy: a dermoscopic pathological study
Authors: S-T. Cheng, C-L.K. Ke, C-H. Lee, C-S. Wu, G-S. Chen, S.C-S. Hu
Journal: British Journal of Dermatology (2008)

We found previously that the features of Kaposi's sarcoma (KS) under polarized dermoscopy are characterized by a bluish-reddish coloration, a scaly surface, small brown globules and, most distinctively, the multicoloured 'rainbow pattern'.To evaluate the significance of the rainbow pattern on dermoscopy as a diagnostic feature in KS, and to demonstrate that it is associated with the unique vascular structure of the tumour.More than 100 lesions from seven patients with histologically proven KS were examined with polarized light dermoscopy. Sixty-three patients with various other cutaneous vascular and nonvascular tumours were also examined. KS lesions exhibiting the rainbow pattern and KS lesions lacking the rainbow pattern on dermoscopy were excised, and dermoscopic features were compared with histopathological structures. The dermoscopic patterns of other vascular tumours were also compared with histological features. In addition, the changes in dermoscopic features and histological structures were assessed before and after surgical therapy in one patient with KS.On the basis of evaluations with polarized dermoscopy, the rainbow pattern was found to be a highly specific dermoscopic feature for KS. Histology of KS lesions showing the rainbow pattern under polarized light dermoscopy demonstrated a vascular lumen-rich pattern of closely arranged 'back-to-back' vascular structures, whereas histology of KS lesions without the rainbow pattern showed a vascular lumen-poor pattern with vascular lumina separated further apart by intervening stromal and cellular tissue. Other vascular tumours did not exhibit the rainbow pattern and were characterized histologically by variably sized vascular structures separated by substantial amounts of stromal and cellular tissue. In one patient with KS, disappearance of the rainbow pattern was associated with obliteration of the vascular structure following surgical ablation therapy.The rainbow pattern in KS is associated with the vascular lumen-rich histological subtype, is not manifest in the vascular lumen-poor subtype and disappears following total tumour removal. Therefore, the underlying structural arrangement of the vessels in KS may determine whether or not the rainbow pattern can be seen on polarized dermoscopy.
I<scp>RON</scp>S<scp>TATUS AND</scp>N<scp>EURAL</scp>F<scp>UNCTIONING</scp>
Authors: John L. Beard, James R. Connor
Journal: Annual Review of Nutrition (2003)

Iron deficiency in early life is associated with delayed development as assessed by a number of clinical trials using similar global scales of development; this poor development during infancy persists in most cases after iron therapy has corrected iron status. If iron deficiency occurs in preschool and older children, the consequences appear reversible with treatment. The biologic understanding of this relationship between development, brain iron status, and functioning is sparse though animal studies repeatedly demonstrate alterations in dopamine metabolism and in the myelination process. Dietary iron deficiency can rapidly deplete brain iron concentrations and repletion is able to normalize them. Residual alterations in striatal dopamine metabolism and myelin production persist if neonatal animals are used. Future studies with more specific measures of neurodevelopment in iron-deficient human infants, and animal models, will allow investigators to more clearly define causal roles of brain iron in neural development and functioning.
Prognostic Significance of Left Ventricular Mass Change During Treatment of Hypertension
Authors: Richard B. Devereux
Journal: JAMA (2004)

Increased baseline left ventricular (LV) mass predicts cardiovascular (CV) complications of hypertension, but the relation between lower LV mass and outcome during treatment for hypertension is uncertain.To determine whether reduction of LV mass during antihypertensive treatment modifies risk of major CV events independent of blood pressure change.Prospective cohort substudy of the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) randomized clinical trial, conducted from 1995 to 2001. A total of 941 prospectively identified patients aged 55 to 80 years with essential hypertension and electrocardiographic LV hypertrophy had LV mass measured by echocardiography at enrollment in the LIFE trial and thereafter were followed up annually for a mean (SD) of 4.8 (1.0) years for CV events.Composite end point of CV death, fatal or nonfatal myocardial infarction, and fatal or nonfatal stroke.The composite end point occurred in 104 patients (11%). The multivariable Cox regression model showed a strong association between lower in-treatment LV mass index and reduced rate of the composite CV end point (hazard ratio [HR], 0.78 per 1-SD (25.3) decrease in LV mass index; 95% confidence interval [CI], 0.65-0.94; P = .009) over and above that predicted by reduction in blood pressure. There were parallel associations between lower in-treatment LV mass index and lower CV mortality (HR, 0.62; 95% CI, 0.47-0.82; P = .001), stroke (HR, 0.76; 95% CI, 0.60-0.96; P = .02), myocardial infarction (HR, 0.85; 95% CI, 0.62-1.17, P = .33), and all-cause mortality (HR, 0.72; 95% CI, 0.59-0.88, P = .002), independent of systolic blood pressure and assigned treatment. Results were confirmed in analyses adjusting for additional CV risk factors, electrocardiographic changes, or when only considering events after the first year of study treatment.In patients with essential hypertension and baseline electrocardiographic LV hypertrophy, lower LV mass during antihypertensive treatment is associated with lower rates of clinical end points, additional to effects of blood pressure lowering and treatment modality.
Altered elimination of antipyrine in patients with acute viral hepatitis.
Authors: D A Burnett, A J Barak, D J Tuma, M F Sorrell
Journal: Gut (1976)

The plasma half-life and clearance of antipyrine was investigated in patients during the acute phase and again during the recovery phase of viral hepatitis. Each patient served as his own control, thereby eliminating genetic factors and minimising environmental factors that cause large interindividual variations in antipyrine elimination rates. Liver function tests, antipyrine, half-life, plasma clearance, and the apparent volume of distribution were determined in the acute and recovery period. It was found that the appaarent volume of distribution of antipyrine did not change in five of six patients as they recovered. Five of the six patients showed prolonged plasma half-lives and decreased plasma clearance of the drug at the time of acute illness and these parameters reached normal values during recovery. The plasma half-life and clearance of the drug did not correlate with biochemical indices of liver function in the recovery phase. This demonstration supports the concept that drug metabolism is frequently impaired in liver disease.
A variable number of tandem repeats locus within the human complement C2 gene is associated with a retroposon derived from a human endogenous retrovirus.
Authors: Z B Zhu, S L Hsieh, D R Bentley, R D Campbell, J E Volanakis
Journal: The Journal of Experimental Medicine (1992)

We have previously described multiallelic restriction fragment length polymorphisms of the C2 gene, suggesting the presence of a variable number of tandem repeats (VNTR) locus. We report here the cloning and sequencing of the polymorphic fragments from the two most common alleles of the gene, a and b. The results confirm the presence of a VNTR locus consisting of a nucleotide sequence, 41 bp in average length, repeated tandemly 23 and 17 times in alleles a and b, respectively. The difference in the number of repeats between the two alleles is due to the deletion/insertion of two noncontiguous segments, 143 and 118 bp long, of allele a, and of a 40-bp segment of allele b. The VNTR region is associated with a SINE (short interspersed sequence)-type retroposon, SINE-R.C2, located within the third intron of the C2 gene. SINE-R.C2 is a member of a previously described large retroposon family of the human genome, apparently derived from the human endogenous retrovirus, (HERV) K10, which is homologous to the mouse mammary tumor virus.
Fusion of ETV6 to Neurotrophin-3 Receptor TRKC in Acute Myeloid Leukemia With t(12;15)(p13;q25)
Authors: Mariko Eguchi, Minenori Eguchi-Ishimae, Arinobu Tojo, Kazuhiro Morishita, Katsuyuki Suzuki, Yuko Sato, Shiori Kudoh, Kimio Tanaka, Misao Setoyama, Fumitaka Nagamura, Shigetaka Asano, Nanao Kamada
Journal: Blood (1999)