tbuckley/cabot-search huggingface dataset:
No objective benefit from steroids inhaled via a spacerin infants recovering from bronchiolitis
Authors: J Y Wong, S Moon, C Beardsmore, C O'Callaghan, H Simpson
Journal: European Respiratory Journal (2000)

A double-blind randomized placebo-controlled trial was conducted to investigate the efficacy of 3 months' inhaled steroids delivered via a spacer device with face mask attachment to infants recovering from bronchiolitis. Forty-eight previously healthy infants recovering from their first documented episode of acute bronchiolitis were randomized to receive 150 microg fluticasone propionate (FP) b.i.d. or placebo delivered via the Babyhaler spacer. Longitudinal assessments were performed on seven occasions over 1 yr based on symptom diaries and health records, clinical examinations, overnight cough recordings and oxygen saturation readings. Lung function was measured 6 months after hospital discharge. Forty-three infants completed the trial (FP 21, placebo 22). There were no significant differences in the three objective end-points measured, recorded night cough, oxygen saturation and lung function test results. Symptom scores were low in both the FP and placebo groups with the absence of (0) or mild (1) symptoms > or =90% of the trial days. No statistical differences in symptom frequency, use of rescue respiratory medications or hospital admissions between treatment groups were found throughout the trial or follow-up periods. In conclusion, the use of inhaled fluticasone propionate in infants recovering from acute bronchiolitis cannot be recommended.
Androgen Receptor–Dependent PSA Expression in Androgen-Independent Prostate Cancer Cells Does Not Involve Androgen Receptor Occupancy of the <i>PSA</i> Locus
Authors: Li Jia, Gerhard A. Coetzee
Journal: Cancer Research (2005)

Abstract It is widely suspected that androgen-independent prostate cancer growth depends on androgen receptor signaling via ill-defined mechanisms. Prostate-specific antigen (PSA) expression is often used to measure androgen receptor activity in cells and prostate cancer progression in patients. In the present study, we have compared androgen receptor activity using PSA and human male germ cell–associated kinase (hMAK), as read-outs in androgen-dependent LNCaP and androgen-independent C4-2B cells. As expected, very little PSA and hMAK expression were detected in LNCaP cells in the absence of androgens, whereas substantial expression of PSA was observed only in C4-2B cells under the same conditions. The addition of dihydrotestosterone to the culture medium increased the expression of both genes in both cell types. Comprehensive chromatin immunoprecipitation analysis of the entire PSA locus and an androgen-response element in hMAK unexpectedly revealed that androgen receptor was not occupying any site in the absence of dihydrotestosterone in either cell type. In line with the expression data, and in the absence of dihydrotestosterone, histone acetylation and RNA polymerase II occupancy was substantial at the PSA locus in C4-2B but not in LNCaP cells. In the presence of dihydrotestosterone, androgen receptor was found to occupy mainly the enhancer region of PSA in both cell types, accompanied with increases in histone acetylation and RNA polymerase II occupancy. Although the androgen receptor was not directly involved in the androgen-independent expression of PSA in C4-2B cells, small interfering RNA knock-down of androgen receptor significantly reduced PSA expression in both the presence and absence of dihydrotestosterone. In contrast, hMAK expression was decreased only in the presence of dihydrotestosterone after androgen receptor knock-down. We conclude that androgen-independent expression of PSA in C4-2B cells does not rely on the direct occupancy of the androgen receptor at the PSA locus, but is nevertheless affected indirectly via unknown androgen receptor–dependent mechanism(s) that influence the expression from some but not all androgen receptor target genes.
Antiangiogenic and Antifibrotic Gene Therapy in a Chronic Infusion Model of Peritoneal Dialysis in Rats
Authors: Peter J. Margetts, Steve Gyorffy, Martin Kolb, Lisa Yu, Catherine M. Hoff, Clifford J. Holmes, Jack Gauldie
Journal: Journal of the American Society of Nephrology (2002)

To identify the relative importance of peritoneal fibrosis and angiogenesis in peritoneal membrane dysfunction, adenoviral mediated gene transfer of angiostatin, a recognized angiogenesis inhibitor, and decorin, a transforming growth factor-beta-inhibiting proteoglycan, were used in a daily infusion model of peritoneal dialysis. A peritoneal catheter and subcutaneous port were inserted in rats. Five and fourteen d after insertion, adenovirus-expressing angiostatin, decorin, or AdDL70, a null control virus, were administered. Daily infusion of 4.25% Baxter Dianeal was initiated 7 d after catheter insertion and continued until day 35. Three initial doses of lipopolysaccharide were administered on days 8, 10, and 12 to promote an inflammatory response. Net ultrafiltration was used as a measure of membrane function, and peritoneum-associated vasculature and mesenteric collagen content was quantified. Ultrafiltration dysfunction, angiogenesis, and fibrosis were observed in daily infusion control animals. Animals treated with AdAngiostatin demonstrated an improvement in net ultrafiltration (-3.1 versus -7.8 ml for control animals; P = 0.0004) with a significant reduction in vessel density. AdDecorin-treated animals showed a reduction in mesenteric collagen content (1.8 versus 2.9 microg/mg; P = 0.04); however, AdDecorin treatment had no effect on net ultrafiltration. In a rodent model of peritoneal membrane failure, net ultrafiltration was significantly improved and peritoneal-associated blood vessels were significantly reduced by using adenovirus-mediated gene transfer of angiostatin. Decorin, a transforming growth factor-beta-inhibiting proteoglycan, reduced collagen content but did not affect net ultrafiltration. Improvement in the function of the peritoneum as a dialysis membrane after treatment with angiostatin has implications for treatment of peritoneal membrane dysfunction seen in patients on long-term dialysis.
Clinical Classification of <i>BRCA1</i> DNA Missense Variants: H1686Q Is a Novel Pathogenic Mutation Occurring in the Ontogenetically Invariant THV Motif of the N-Terminal BRCT Domain
Authors: Giuseppe Giannini, Carlo Capalbo, Laura Ottini, Amelia Buffone, Laura De Marchis, Elena Margaria, Domenico Vitolo, Enrico Ricevuto, Christian Rinaldi, Massimo Zani, Sergio Ferraro, Paolo Marchetti, Enrico Cortesi, Luigi Frati, Isabella Screpanti, Alberto Gulino
Journal: Journal of Clinical Oncology (2008)
"Bubble baby" lives a normal life after gene therapy
Authors: O. Dyer
Journal: BMJ (2002)

The first success for gene therapy in the United Kingdom has restored health to an infant who last year was confined to a sterile room and needed to be kept alive by a ventilator.

Rhys Evans, now 18 months old, suffered from X chromosome linked severe combined immunodeficiency disorder, popularly known as “baby in the bubble” syndrome, after the sterile plastic spheres used to protect some babies from infection. He now lives a normal life at home.

At a …
Lack of Widespread BBB Disruption in Alzheimer’s Disease Models: Focus on Therapeutic Antibodies
Authors: Nga Bien-Ly, C. Andrew Boswell, Surinder Jeet, Thomas G. Beach, Kwame Hoyte, Wilman Luk, Vera Shihadeh, Sheila Ulufatu, Oded Foreman, Yanmei Lu, Jason DeVoss, Marcel van der Brug, Ryan J. Watts
Journal: Neuron (2015)
Increased levels of the chemokines GROalpha and MCP-1 in sputum samples from patients with COPD
Authors: S L Traves, S V Culpitt, R E K Russell, P J Barnes, L E Donnelly
Journal: Thorax (2002)

<b>Background:</b> Patients with chronic obstructive pulmonary disease (COPD) have increased numbers of neutrophils and macrophages in their lungs. Growth related oncogene-α (GROα) attracts neutrophils, whereas monocyte chemoattractant protein-1 (MCP-1) attracts monocytes that can differentiate into macrophages. The aim of this study was to determine the concentration of GROα and MCP-1 in bronchoalveolar lavage (BAL) fluid and sputum from non-smokers, healthy smokers and patients with COPD, and to see if there was a correlation between the concentrations of these chemokines, lung function, and numbers of inflammatory cells. <b>Methods:</b> BAL fluid and sputum from non-smokers (n=32), healthy smokers (n=36), and patients with COPD (n=40) were analysed for the presence of GROα and MCP-1 using ELISA. Cells counts were performed on the samples and correlations between the concentrations of these chemokines, lung function, and inflammatory cells observed. <b>Results:</b> Median (SE) GROα and MCP-1 levels were significantly increased in sputum from patients with COPD compared with non-smokers and healthy smokers (GROα: 31 (11) <i>v</i> 2 (2) <i>v</i> 3 (0.8) ng/ml; MCP-1: 0.8 (0.4) <i>v</i> 0.2 (0.1) <i>v</i> 0.1 (0.04) ng/ml, p&lt;0.05), but not in BAL fluid. There were significant negative correlations between both GROα and MCP-1 levels in sputum and forced expiratory volume in 1 second (FEV<sub>1</sub>) % predicted (GROα: <i>r</i>=–0.5, p&lt;0.001; MCP-1: <i>r</i>=–0.5, p&lt;0.001), together with significant positive correlations between GROα and MCP-1 and neutrophil numbers in sputum (GROα: <i>r</i>=0.6, p&lt;0.001; MCP-1: <i>r</i>=0.4, p&lt;0.01). <b>Conclusion:</b> These results suggest that GROα and MCP-1 are involved in the migration of inflammatory cells, thus contributing to the inflammatory load associated with COPD.
Fractalkine Preferentially Mediates Arrest and Migration of CD16+ Monocytes
Authors: Petronela Ancuta, Ravi Rao, Ashlee Moses, Andrew Mehle, Sunil K. Shaw, F. William Luscinskas, Dana Gabuzda
Journal: The Journal of Experimental Medicine (2003)

CD16+ monocytes represent 5–10% of peripheral blood monocytes in normal individuals and are dramatically expanded in several pathological conditions including sepsis, human immunodeficiency virus 1 infection, and cancer. CD16+ monocytes produce high levels of proinflammatory cytokines and may represent dendritic cell precursors in vivo. The mechanisms that mediate the recruitment of CD16+ monocytes into tissues remain unknown. Here we investigate molecular mechanisms of CD16+ monocyte trafficking and show that migration of CD16+ and CD16− monocytes is mediated by distinct combinations of adhesion molecules and chemokine receptors. In contrast to CD16− monocytes, CD16+ monocytes expressed high CX3CR1 and CXCR4 but low CCR2 and CD62L levels and underwent efficient transendo-thelial migration in response to fractalkine (FKN; FKN/CX3CL1) and stromal-derived factor 1α (CXCL12) but not monocyte chemoattractant protein 1 (CCL2). CD16+ monocytes arrested on cell surface–expressed FKN under flow with higher frequency compared with CD16− monocytes. These results demonstrate that FKN preferentially mediates arrest and migration of CD16+ monocytes and suggest that recruitment of this proinflammatory monocyte subset to vessel walls via the CX3CR1-FKN pathway may contribute to vascular and tissue injury during pathological conditions.
Does Treatment Intensity Matter in Superficial Bladder Cancer? Consensus, Clinical Practice, and Confounding
Authors: G. H. Lyman, N. M. Kuderer, S. J. Freedland
Journal: JNCI Journal of the National Cancer Institute (2009)

The majority of patients who are diagnosed with bladder cancer initially present with noninvasive disease (1). Nevertheless, 40%–80% of patients diagnosed with superficial bladder cancers will experience a recurrence, including 10%–25% of those with potentially lethal muscle-invasive disease, within the first 3 years after diagnosis (2–4). Current guidelines from the American Urologic Association (5,6) and the National Comprehensive Cancer Network (5,6) recommend frequent cystoscopic surveillance of patients diagnosed with superficial bladder cancer. However, physicians treating patients with superficial bladder cancer vary widely in their adherence to surveillance guidelines (7). Practical and ethical considerations that preclude randomized controlled trials to establish the impact of surveillance on survival of patients with superficial bladder cancer include the high recurrence rate, the ability of cystoscopic surveillance to identify recurrence early, the demonstrated efficacy of local therapy in preventing or delaying the development of muscle-invasive disease, and the overall poor prognosis of muscle-invasive disease (7–10).
Nucleosome rotational setting is associated with transcriptional regulation in promoters of tissue-specific human genes
Authors: Charles Hebert, Hugues Roest Crollius
Journal: Genome biology (2010)

Abstract Background The position of a nucleosome, both translational along the DNA molecule and rotational between the histone core and the DNA, is controlled by many factors, including the regular occurrence of specific dinucleotides with a period of approximately 10 bp, important for the rotational setting of the DNA around the histone octamer. Results We show that such a 10 bp periodic signal of purine-purine dinucleotides occurs in phase with the transcription start site (TSS) of human genes and is centered on the position of the first (+1) nucleosome downstream of the TSS. These data support a direct link between transcription and the rotational setting of the nucleosome. The periodic signal is most prevalent in genes that contain CpG islands that are expressed at low levels in a tissue-specific manner and are involved in the control of transcription. Conclusions These results, together with several lines of evidence from the recent literature, support a new model whereby the +1 nucleosome could be more efficiently disassembled from gene promoters by H3K56 acetylation marks if the periodic signal specifies an optimal rotational setting.
Management of Seminomatous Testicular Cancer: A Binational Prospective Population-Based Study From the Swedish Norwegian Testicular Cancer Study Group
Authors: Torgrim Tandstad, Rune Smaaland, Arne Solberg, Roy M. Bremnes, Carl W. Langberg, Anna Laurell, Ulrika K. Stierner, Olof Ståhl, Eva K. Cavallin-Ståhl, Olbjørn H. Klepp, Olav Dahl, Gabriella Cohn-Cedermark
Journal: Journal of Clinical Oncology (2011)

Purpose A binational, population-based treatment protocol was established to prospectively treat and follow patients with seminomatous testicular cancer. The aim was to standardize care for all patients with seminoma to further improve the good results expected for this disease. Patients and Methods From 2000 to 2006, a total of 1,384 Norwegian and Swedish patients were included in the study. Treatment in clinical stage 1 (CS1) was surveillance, adjuvant radiotherapy, or adjuvant carboplatin. In metastatic disease, recommended treatment was radiotherapy in CS2A and cisplatin-based chemotherapy in CS2B or higher. Results At a median follow-up of 5.2 years, 5-year cause-specific survival was 99.6%. In CS1, 14.3% (65 of 512) of patients relapsed following surveillance, 3.9% (seven of 188) after carboplatin, and 0.8% (four of 481) after radiotherapy. We could not identify any factors predicting relapse in CS1 patients who were subjected to surveillance only. In CS2A, 10.9% (three of 29) patients relapsed after radiotherapy compared with no relapses in CS2A/B patients (zero of 73) treated with chemotherapy (P = .011). Conclusion An international, population-based treatment protocol for testicular seminoma is feasible with excellent results. Surveillance remains a good option for CS1 patients. No factors predicted relapse in CS1 patients on surveillance. Despite resulting in a lower rate of relapse than with adjuvant carboplatin, adjuvant radiotherapy has been abandoned in the Swedish and Norwegian Testicular Cancer Project (SWENOTECA) as a recommended treatment option because of concerns of induction of secondary cancers. The higher number of relapses in radiotherapy-treated CS2A patients when compared with chemotherapy-treated CS2A/B patients is of concern. Late toxicity of cisplatin-based chemotherapy versus radiotherapy must be considered in CS2A patients.
Signet-Ring Cell or Mucinous Histology after Preoperative Chemoradiation and Survival in Patients with Esophageal or Esophagogastric Junction Adenocarcinoma
Authors: Lucian R. Chirieac, Stephen G. Swisher, Arlene M. Correa, Jaffer A. Ajani, Ritsuko R. Komaki, Asif Rashid, Stanley R. Hamilton, Tsung-Teh Wu
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The survival of patients with local-regional adenocarcinoma of the esophagus or esophagogastric junction (EGJ) treated with preoperative chemoradiation is much better in patients with pathologic complete response than those with residual tumor. Some adenocarcinomas have mixed patterns, including signet-ring cell and mucinous histology, but the clinical significance of these subtypes is unknown. Experimental Design: We studied 412 consecutive patients with esophageal or EGJ adenocarcinoma treated with chemoradiation followed by esophagectomy (193 patients) or surgery alone (219 patients). We evaluated signet-ring cell and mucinous histology in the resection and pretherapy biopsy specimens and compared clinicopathologic features with overall survival. Results: The fraction of signet-ring cell and mucinous histology was similar in evaluated specimens of patients treated with preoperative chemoradiation or surgery alone (17% and 18%, respectively). The overall survival rate at 5 years of patients treated with preoperative chemoradiation was significantly better if residual signet-ring cell or mucinous histology was present in the esophagectomy specimen (63% versus 28%; P = 0.02). All 13 patients with acellular mucin pools and no residual carcinoma are still alive after an average follow-up time of 36 months. By contrast, in patients treated with surgery alone, overall survival rate was significantly worse if signet-ring cell or mucinous histology was present (14% versus 30%; P = 0.05). In multivariate analysis, overall survival was independently predicted by presence of signet-ring cell or mucinous histology (P = 0.04). Conclusions: Our study showed that patients with esophageal or EGJ adenocarcinoma who have signet-ring cell or mucinous histology benefited substantially from preoperative chemoradiation and esophagectomy.
Role of extracellular matrix in regulating fenestrations of sinusoidal endothelial cells isolated from normal rat liver
Authors: Richard F. McGuire, Montgomery D. Bissell, Janet Boyles, Joseph F. Roll
Journal: Hepatology (1992)

Open fenestrations are a conspicuous feature of sinusoidal endothelial cells and allow free movement of plasma into the space of Disse. In hepatic fibrosis, the number of fenestrations decreases as interstitial collagen increases in the liver, a change that correlates with deposition of extracellular matrix in the space of Disse. In this study, the possibility of a causal relationship between altered fenestral morphology and perisinusoidal matrix has been examined by culturing rat sinusoidal endothelial cells on individual matrix proteins or on a native matrix consisting of human amniotic membrane with interstitial collagen (types I and III) on one side and basement membrane proteins (collagen types IV and V and laminin) on the other. Under culture conditions, individual components of the extracellular matrix failed to maintain fenestrations. A basement–membranelike gel matrix derived from the Engelbreth–Holm–Swarm tumor was similarly ineffective. Fenestral density and porosity (percentage of cell surface occupied by fenestrations) were significantly enhanced, however, when endothelial cells were cultured on the basement–membrane side of human amnion. These data suggest that support of endothelial fenestrations requires a complex matrix. In particular, physiologically derived basement membrane maintains fenestrations, whereas interstitial collagen matrix does not. The loss of fenestrations associated with hepatic fibrosis may be related in part to an accumulation of interstitial collagens in the space of Disse. (Hepatology 1992;15:989–997).
The Mitogen-Activated Protein Kinase Phosphatase <i>Vaccinia</i> H1–Related Protein Inhibits Apoptosis in Prostate Cancer Cells and Is Overexpressed in Prostate Cancer
Authors: Yke Jildouw Arnoldussen, Petra I. Lorenzo, Maria E. Pretorius, Håkon Wæhre, Bjørn Risberg, Gunhild M. Mælandsmo, Håvard E. Danielsen, Fahri Saatcioglu
Journal: Cancer Research (2008)

Abstract Androgen ablation during the initial stages of prostate cancer causes regression of the tumor due to an increase in apoptosis and reduced cellular proliferation. However, prostate cancer invariably progresses to an androgen-independent state for poorly understood reasons. Previous studies showed that c-Jun NH2 terminal kinase (JNK) is required for 12-O-tetradecanoylphorbol-13-acetate (TPA)– and thapsigargin (TG)–induced apoptosis in the androgen-responsive prostate cancer cell line LNCaP. Androgens protect LNCaP cells from TPA-induced or TG-induced apoptosis via down-regulation of JNK activation. However, the molecular mechanisms of this inhibition are not clear. Here, we systematically investigated the possible regulation of mitogen-activated protein kinase phosphatases/dual-specificity phosphatases during apoptosis of LNCaP cells and found that Vaccinia H1–related protein (VHR/DUSP3) is up-regulated by androgens during inhibition of apoptosis in LNCaP cells, but not in androgen-independent DU145 cells. Ectopic expression of wild-type VHR, but not a catalytically inactive mutant, interfered with TPA- and TG-induced apoptosis. Consistently, small interfering RNA–mediated knockdown of endogenous VHR increased apoptosis in response to TPA or TG in the presence of androgens. Furthermore, COS7 cells stably expressing wild-type VHR, but not a mutant, had a decrease in JNK phosphorylation. In vivo, VHR expression decreased in the androgen-dependent human prostate cancer xenograft CWR22 upon androgen withdrawal and was inversely correlated to JNK phosphorylation. Expression analysis in human prostate cancer specimens showed that VHR is increased in prostate cancer compared with normal prostate. These data show that VHR has a direct role in the inhibition of JNK-dependent apoptosis in LNCaP cells and may therefore have a role in prostate cancer progression. [Cancer Res 2008;68(22):9255–64]
European Respiratory Society study on chronic obstructive pulmonary disease (EUROSCOP): hypothesis and design
Authors: RA Pauwels, CG Lofdahl, NB Pride, DS Postma, LA Laitinen, SV Ohlsson
Journal: European Respiratory Journal (1992)

Chronic obstructive pulmonary disease (COPD) is a common disease in industrialised countries and responsible for a considerable morbidity and mortality. Cigarette smoking is the most important aetiological factor. The EUROSCOP trial aims at investigating the hypothesis that airway inflammation plays an important pathogenic role in the development of chronic obstructive airway disease in smokers. In cigarette smokers with poorly reversible airflow obstruction, the effect over 3 yrs of an inhaled glucocorticosteroid, budesonide 400 micrograms b.i.d., on the decline of lung function, measured as postbronchodilator forced expiratory volume in one second (FEV1), will be compared with that of placebo. The trial has been designed to detect a difference in yearly decline of at least 30 ml.year-1. The study is a parallel group, randomised, double-blind, multicentre study. Patients will be recruited from 47 centres in 12 countries in Europe. It will start with a run-in consisting of two 3 month periods. During the first 3 months, the patients will be offered a smoking cessation programme. All patients who have not stopped smoking during this period will enter the second half of the run-in where compliance with the dosage regimen will be tested. After these two periods, patients will be randomised to receive either inhaled budesonide, 400 micrograms b.i.d., or placebo for a period of 3 yrs.