tbuckley/cabot-search huggingface dataset:
ERK and p38 MAPK, but not NF-κB, Are Critically Involved in Reactive Oxygen Species–Mediated Induction of IL-6 by Angiotensin II in Cardiac Fibroblasts
Authors: Motoaki Sano, Keiichi Fukuda, Toshihiko Sato, Haruko Kawaguchi, Makoto Suematsu, Satoshi Matsuda, Shigeo Koyasu, Hideo Matsui, Keiko Yamauchi-Takihara, Masaki Harada, Yoshihiko Saito, Satoshi Ogawa
Journal: Circulation Research (2001)

We recently reported that angiotensin II (Ang II) induced IL-6 mRNA expression in cardiac fibroblasts, which played an important role in Ang II–induced cardiac hypertrophy in paracrine fashion. The present study investigated the regulatory mechanism of Ang II–induced IL-6 gene expression, focusing especially on reactive oxygen species (ROS)-mediated signaling in cardiac fibroblasts. Ang II increased intracellular ROS in cardiac fibroblasts, and the increase was completely inhibited by the AT-1 blocker candesartan and the NADH/NADPH oxidase inhibitor diphenyleneiodonium (DPI). We first confirmed that antioxidant N -acetylcysteine, superoxide scavenger Tiron, and DPI suppressed Ang II–induced IL-6 expression. Because we observed that exogenous H 2 O 2 also increased IL-6 mRNA, the signaling pathways downstream of Ang II and exogenous H 2 O 2 were compared. Ang II, as well as exogenous H 2 O 2 , activated ERK, p38 MAPK, and JNK, which were significantly inhibited by N -acetylcysteine and DPI. In contrast with exogenous H 2 O 2 , however, Ang II did not influence phosphorylation and degradation of IκB-α/β or nuclear translocation of p65, nor did it increase NF-κB promoter activity. PD98059 and SB203580 inhibited Ang II–induced IL-6 expression. Truncation and mutational analysis of the IL-6 gene promoter showed that CRE was an important cis -element in Ang II–induced IL-6 gene expression. NF-κB–binding site was important for the basal expression of IL-6, but was not activated by Ang II. Ang II phosphorylated CREB through the ERK and p38 MAPK pathway in a ROS-sensitive manner. Collectively, these data indicated that Ang II stimulated ROS production via the AT1 receptor and NADH/NADPH oxidase, and that these ROS mediated activation of MAPKs, which culminated in IL-6 gene expression through a CRE-dependent, but not NF-κB–dependent, pathway in cardiac fibroblasts.
Sustained signaling leading to T cell activation results from prolonged T cell receptor occupancy. Role of T cell actin cytoskeleton.
Authors: S Valitutti, M Dessing, K Aktories, H Gallati, A Lanzavecchia
Journal: The Journal of Experimental Medicine (1995)

Using antigen-specific T cell clones and peptide-pulsed antigen-presenting cells (APCs) we investigated the mechanisms that lead to sustained signaling, known to be required for activation of effector function. Four lines of evidence indicate that the T cell actin cytoskeleton plays a crucial role in T cell activation by antigen-pulsed APCs, but is not required when T cell receptor (TCR) is cross-linked by soluble antibodies. First, addition of antibodies to the major histocompatibility complex molecules recognized by the TCR aborts the ongoing intracellular calcium concentration ([Ca2+]i) increase in performed T-APC conjugates, indicating that the sustained signaling requires the continuous occupancy of TCR. Second, time-lapse image recording shows that T lymphocytes conjugated to peptide-pulsed APCs undergo a sustained [Ca2+]i increase, which is accompanied by the formation of a large and changing area of contact between the two opposing membranes. Third, drugs that disrupt the actin cytoskeleton, Cytochalasin D and and C2 Clostridium botulinum toxin induce a rapid block of [Ca2+]i rise, coincident with a block of the cyclic changes in T cell shape. Finally, the addition of Cytochalasin D or of anti-MHC antibodies to preformed conjugates inhibits interferon gamma production in an 1-antigen dose- and time-dependent fashion. These results identify T cell actin cytoskeleton as a major motor for sustaining signal transduction and possibly for driving TCR cross-linking and offer an explanation for how T cells equipped with low affinity TCR can be triggered by a small number of complexes on APCs.
Hormone Replacement Therapy and Physical Function in Healthy Older Men. Time to Talk Hormones?
Authors: Manthos G. Giannoulis, Finbarr C. Martin, K. Sreekumaran Nair, A. Margot Umpleby, Peter Sonksen
Journal: Endocrine Reviews (2012)

Improving physical function and mobility in a continuously expanding elderly population emerges as a high priority of medicine today. Muscle mass, strength/power, and maximal exercise capacity are major determinants of physical function, and all decline with aging. This contributes to the incidence of frailty and disability observed in older men. Furthermore, it facilitates the accumulation of body fat and development of insulin resistance. Muscle adaptation to exercise is strongly influenced by anabolic endocrine hormones and local load-sensitive autocrine/paracrine growth factors. GH, IGF-I, and testosterone (T) are directly involved in muscle adaptation to exercise because they promote muscle protein synthesis, whereas T and locally expressed IGF-I have been reported to activate muscle stem cells. Although exercise programs improve physical function, in the long-term most older men fail to comply. The GH/IGF-I axis and T levels decline markedly with aging, whereas accumulating evidence supports their indispensable role in maintaining physical function integrity. Several studies have reported that the administration of T improves lean body mass and maximal voluntary strength in healthy older men. On the other hand, most studies have shown that administration of GH alone failed to improve muscle strength despite amelioration of the detrimental somatic changes of aging. Both GH and T are anabolic agents that promote muscle protein synthesis and hypertrophy but work through separate mechanisms, and the combined administration of GH and T, albeit in only a few studies, has resulted in greater efficacy than either hormone alone. Although it is clear that this combined approach is effective, this review concludes that further studies are needed to assess the long-term efficacy and safety of combined hormone replacement therapy in older men before the medical rationale of prescribing hormone replacement therapy for combating the sarcopenia of aging can be established.
Outcome of sports injuries treated in a casualty department.
Authors: J Sandelin, O Kiviluoto, S Santavirta, R Honkanen
Journal: British Journal of Sports Medicine (1985)

The present investigation analyses 2493 patients with a sports injury treated in a casualty department during a one-year period. Of the patients 73% were men, the age of the patients averaging 26 years and the mean follow-up time was 24 months. Soccer and indoor ball games caused 24% and 23% of the injuries respectively, these being followed by injuries in ice hockey in 14%. Track and field injuries scored low with 2% out of all injuries. Injuries to the lower extremity predominated. At follow-up, ligamentous injuries of the lower extremity were the major cause of discomfort. Further, in the group of patients with persistent discomfort 36% had suffered a fracture or a dislocation, 13% a contusion and 10% a wound. The mean period of sports incapacity after a sustained injury was 3 weeks. In track and field events the injury seldom disturbed training for more than one week, but in soccer, indoor ball games, skiing and skating the mean sports incapacity period varied between 6 and 3 weeks. Out of the total injured, 2% had to give up their sports activity completely. An injury of the lower extremity demanded on average 4 weeks' rest, an injury of the upper extremity and the trunk 2 weeks and injuries of the head and neck one week's rest. According to the present investigation sports injuries were in the majority of cases of a relatively benign nature and sick leave from work seldom exceeded 2 weeks.
Matching of Soulmates: Coevolution of snoRNAs and Their Targets
Authors: S. Kehr, S. Bartschat, H. Tafer, P. F. Stadler, J. Hertel
Journal: Molecular Biology and Evolution (2013)

Ribosomal and small nuclear RNAs (snRNAs) comprise numerous modified nucleotides. The modification patterns are retained during evolution, making it even possible to project them from yeast onto human. The stringent conservation of modification sites and the slow evolution of rRNAs and snRNAs contradicts the rapid evolution of small nucleolar RNA (snoRNA) sequences. To explain this discrepancy, we investigated the coevolution of snoRNAs and their targeted sites throughout vertebrates. To measure and evaluate the conservation of RNA-RNA interactions, we defined the interaction conservation index (ICI). It combines the quality of individual interaction with the scope of its conservation in a set of species and serves as an efficient measure to evaluate the conservation of the interaction of snoRNA and target. We show that functions of homologous snoRNAs are evolutionarily stable, thus, members of the same snoRNA family guide equivalent modifications. The conservation of snoRNA sequences is high at target binding regions while the remaining sequence varies significantly. In addition to elucidating principles of correlated evolution, we were able, with the help of the ICI measure, to assign functions to previously orphan snoRNAs and to associate snoRNAs as partners to known chemical modifications unassigned to a given snoRNA. Furthermore, we used predictions of snoRNA functions in conjunction with sequence conservation to identify distant homologies. Because of the high overall entropy of snoRNA sequences, such relationships are hard to detect by means of sequence homology search methods alone.
Study on the Protective Effect of the KIR3DL1 Gene in Ankylosing Spondylitis
Authors: S. Vendelbosch, S. C. Heslinga, M. John, K. van Leeuwen, J. Geissler, M. de Boer, M. W. T. Tanck, T. K. van den Berg, J. B. A. Crusius, I. E. van der Horst‐Bruinsma, T. W. Kuijpers
Journal: Arthritis & Rheumatology (2015)

Objective Ankylosing spondylitis (AS) is an autoimmune disease that mainly affects the sacroiliac joints and the spine of the lower back. The disease is strongly associated with HLA–B27. Additional genes, single‐nucleotide polymorphisms, and molecular components have been identified to be associated with AS, but the exact mechanism that drives disease development remains poorly understood. The killer cell immunoglobulin‐like receptors (KIRs) are regulators of cytotoxicity of natural killer cells and T cell subsets and may be relevant in binding to HLA–B27 and the development of AS. We undertook this study to identify possible associations of KIR genotype with susceptibility to AS and disease characteristics including the presence of the HLA–B27 allele, disease severity, and uveitis. Methods We performed complete genotyping of the KIR locus in 303 Caucasian AS patients, 119 randomly selected healthy Caucasian controls, and 50 HLA–B27–positive healthy Caucasian controls by multiplex ligation‐dependent probe amplification assay for detection of gene presence and copy number. Results We did not observe a significant association of any specific KIR gene or haplotype with susceptibility to AS or any other clinical manifestation. Disease severity, as measured by fulfilling the criteria for treatment with tumor necrosis factor blocking therapy, was linked to a lower number of genes for the functional variant of KIR3DL1 ( P = 0.007). Conclusion Our exploratory study indicates that KIR genes are not a major risk factor for susceptibility to AS. However, the data do suggest a role for KIRs in progression of the disease, whereby KIR3DL1 has a protective effect against the more severe manifestations of AS.
Potential Role of HE4 in Multimodal Screening for Epithelial Ovarian Cancer
Authors: N. Urban, J. D. Thorpe, L. A. Bergan, R. M. Forrest, A. V. Kampani, N. Scholler, K. C. O'Briant, G. L. Anderson, D. W. Cramer, C. D. Berg, M. W. McIntosh, P. Hartge, C. W. Drescher
Journal: JNCI Journal of the National Cancer Institute (2011)

In screening for epithelial ovarian cancer, unnecessary surgery can be reduced by limiting use of transvaginal ultrasound (TVU) to women with increasing CA125 serum levels. Replacing or augmenting TVU with measurement of a serum marker specific for malignancy might further improve screening performance. Serum samples from 112 invasive ovarian cancer patients and 706 matched control subjects from the Prostate, Lung, Colorectal, and Ovarian trial were used to evaluate human epididymis protein 4 (HE4), mesothelin, matrix metalloproteinase 7 (MMP7), SLPI, Spondin2, and insulin-like growth factor binding protein 2 (IGFBP2) for their potential use in screening. TVU results were available for a subset of 84 patients and 516 control subjects used to compare the best marker with TVU. HE4 was found to perform better than TVU as a second-line screen, confirming 27 of 39 cancers with increasing CA125 serum levels compared with 17 cancers confirmed by TVU ( P = .03). Serum HE4 levels were found to increase with age and smoking status, suggesting that a longitudinal algorithm might improve its performance.
Tight regulation of ubiquitin-mediated DNA damage response by USP3 preserves the functional integrity of hematopoietic stem cells
Authors: Cesare Lancini, Paul C.M. van den Berk, Joseph H.A. Vissers, Gaetano Gargiulo, Ji-Ying Song, Danielle Hulsman, Michela Serresi, Ellen Tanger, Marleen Blom, Conchita Vens, Maarten van Lohuizen, Heinz Jacobs, Elisabetta Citterio
Journal: The Journal of Experimental Medicine (2014)

Histone ubiquitination at DNA breaks is required for activation of the DNA damage response (DDR) and DNA repair. How the dynamic removal of this modification by deubiquitinating enzymes (DUBs) impacts genome maintenance in vivo is largely unknown. To address this question, we generated mice deficient for Ub-specific protease 3 (USP3; Usp3Δ/Δ), a histone H2A DUB which negatively regulates ubiquitin-dependent DDR signaling. Notably, USP3 deletion increased the levels of histone ubiquitination in adult tissues, reduced the hematopoietic stem cell (HSC) reserves over time, and shortened animal life span. Mechanistically, our data show that USP3 is important in HSC homeostasis, preserving HSC self-renewal, and repopulation potential in vivo and proliferation in vitro. A defective DDR and unresolved spontaneous DNA damage contribute to cell cycle restriction of Usp3Δ/Δ HSCs. Beyond the hematopoietic system, Usp3Δ/Δ animals spontaneously developed tumors, and primary Usp3Δ/Δ cells failed to preserve chromosomal integrity. These findings broadly support the regulation of chromatin ubiquitination as a key pathway in preserving tissue function through modulation of the response to genotoxic stress.
P18 Experimental infection with low dose rhinovirus in asthma
Authors: D. Jackson, J. Del Rosario, S. Johnston
Journal: Thorax (2010)

Viral respiratory tract infections are important triggers for exacerbations of asthma and have been found in the majority of wheezing episodes in both children and adults. Of the respiratory tract viruses identified in these circumstances, rhinoviruses are most commonly found. Experimental human models of rhinovirus infection offer great potential for improving our understanding of virus-induced airway inflammation and offer significant opportunity for improved disease management in asthma. Thus far, human experimental infection studies in asthma have used high doses of virus inoculums (10 000 TCID<sub>50</sub>). Using a low dose would better mimic the natural course of infection and in allow a more representative inflammatory response to be studied. In this pilot study, five mild–moderate atopic asthmatic subjects and five non-asthmatic healthy controls all with negative RV-16 serology were infected with 10 TCID<sub>50</sub> RV16. The aim was to establish whether this low dose was suitable for future experimental infection studies. Daily morning peak flow, FEV<sub>1</sub> and symptom scores were recorded until day 10 following inoculation. Nasal lavage for viral load was obtained on day 0, 3, 4, 5, 6, 7 and 10 and measured using Taqman. <h3>Results</h3> 3/5 atopic asthmatic and 3/5 healthy volunteers developed the subjective feeling of a common cold associated with objective evidence of RV16 in their nasal lavage. The three asthmatic subjects also developed lower respiratory symptoms along with an average fall in their peak flow of 86.7 l/min (15.1%) in keeping with an exacerbation. None of the healthy volunteers developed lower respiratory symptoms or had any change in their lung function measurements. <h3>Conclusion</h3> Low-dose RV16 challenge is sufficient to induce clinical signs of an asthma exacerbation in a majority (60%) of asthmatic subjects. A higher dose of virus such as 100 TCID<sub>50</sub> will more likely result in a larger proportion of subjects clinically infected whilst still allowing a more natural course of infection to develop. It is possible that factors other than negative RV16 serology at screening are important determinants of who becomes infected with rhinovirus. Further research is needed to identify what these factors may be.
Phase I Pharmacokinetic and Pharmacodynamic Study of 17-<i>N</i>-Allylamino-17-Demethoxygeldanamycin in Pediatric Patients with Recurrent or Refractory Solid Tumors: A Pediatric Oncology Experimental Therapeutics Investigators Consortium Study
Authors: Rochelle Bagatell, Lia Gore, Merrill J. Egorin, Richard Ho, Glenn Heller, Nichole Boucher, Eleanor G. Zuhowski, James A. Whitlock, Stephen P. Hunger, Aru Narendran, Howard M. Katzenstein, Robert J. Arceci, Jessica Boklan, Cynthia E. Herzog, Luke Whitesell, S. Percy Ivy, Tanya M. Trippett
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Heat shock protein 90 (Hsp90) is essential for the posttranslational control of many regulators of cell growth, differentiation, and apoptosis. 17-N-Allylamino-17-demethoxygeldanamycin (17-AAG) binds to Hsp90 and alters levels of proteins regulated by Hsp90. We conducted a phase I trial of 17-AAG in pediatric patients with recurrent or refractory neuroblastoma, Ewing's sarcoma, osteosarcoma, and desmoplastic small round cell tumor to determine the maximum tolerated dose, define toxicity and pharmacokinetic profiles, and generate data about molecular target modulation. Experimental Design: Escalating doses of 17-AAG were administered i.v. over 1 to 2 h twice weekly for 2 weeks every 21 days until patients experienced disease progression or toxicity. harmacokinetic and pharmacodynamic studies were done during cycle 1. Results: Fifteen patients were enrolled onto dose levels between 150 and 360 mg/m2; 13 patients were evaluable for toxicity. The maximum tolerated dose was 270 mg/m2. DLTs were grade 3 transaminitis and hypoxia. Two patients with osteosarcoma and bulky pulmonary metastases died during cycle 1 and were not evaluable for toxicity. No objective responses were observed. 17-AAG pharmacokinetics in pediatric patients were linear; clearance and half-life were 21.6 ± 6.21 (mean ± SD) L/h/m2 and 2.6 ± 0.95 h, respectively. Posttherapy increases in levels of the inducible isoform of Hsp70, a marker of target modulation, were detected in peripheral blood mononuclear cells at all dose levels. Conclusion: 17-AAG was well tolerated at a dose of 270 mg/m2 administered twice weekly for 2 of 3 weeks. Caution should be used in treatment of patients with bulky pulmonary disease.
<i>KIF14</i> Messenger RNA Expression Is Independently Prognostic for Outcome in Lung Cancer
Authors: Timothy W. Corson, Chang Qi Zhu, Suzanne K. Lau, Frances A. Shepherd, Ming-Sound Tsao, Brenda L. Gallie
Journal: Clinical Cancer Research (2007)

Abstract Purpose: The mitotic kinesin KIF14 is overexpressed in multiple cancers including lung cancer. Therefore, we investigated KIF14 expression in association with clinical variables and the effect of KIF14 on in vitro colony formation in non–small-cell lung carcinoma. Experimental Design: RNA was extracted from 129 untreated, resected tumors and KIF14 expression was quantified by real-time reverse transcription-PCR. Associations with clinical variables were determined by standard statistical methods. KIF14 expression was knocked down by small interfering RNA in H1299 and HeLa cells; proliferation and growth in soft agar were assayed. Results: Squamous cell carcinoma had the highest KIF14 level, followed by large-cell undifferentiated carcinoma, then adenocarcinoma (P = 0.002). KIF14 level decreased with differentiation (P = 0.01) but was not associated with pathologic stage, T or N stage, or sex. When dichotomized about the median, KIF14 overexpression significantly decreased disease-free survival (Kaplan-Meier log-rank, P = 0.01) and trended toward decreasing overall survival (P = 0.08). In a univariate Cox proportional hazard regression, increasing KIF14 expression decreased disease-free survival [P = 0.01; hazard ratio, 1.44 (95% confidence interval, 1.09-1.91)]. In a multivariate Cox regression, including stage, differentiation, histology, and tumor purity as covariates, KIF14 overexpression remained an independent prognostic factor for disease-free survival [P = 0.01; hazard ratio, 1.45 (95% confidence interval, 1.09-1.94)]. Knockdown of KIF14 in non–small-cell lung carcinoma and cervical carcinoma cell lines decreased proliferation and colony formation in soft agar. Conclusions: KIF14 expression is independently prognostic for disease-free survival in lung cancer and knockdown decreases tumorigenicity in vitro, showing that it is a clinically relevant oncogene and an exciting therapeutic target for further study.
p53 expression and K-ras mutation in colorectal adenomas.
Authors: N Scott, S M Bell, P Sagar, G E Blair, M F Dixon, P Quirke
Journal: Gut (1993)

The frequency of p53 overexpression and K-ras codon 12 mutation was investigated in a series of colorectal adenomas. p53 was detected by immunohistochemistry in only 5% of tumours, whereas K-ras mutation was found in eight of 30 adenomas examined. In vitro, mutant p53 and ras genes cooperate to transform primary rat cells into a tumourigenic cell line. The presence of both p53 overexpression and K-ras mutation in a benign tubulovillous polyp in the present series suggests that in vivo this combination of events is insufficient to cause malignant transformation of a large bowel adenoma.
DNase I Acutely Increases Cystic Fibrosis Sputum Elastase Activity and its Potential to Induce Lung Hemorrhage in Mice
Authors: ANDRÉ M. CANTIN
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

The potential of DNase I to increase cystic fibrosis sputum elastase activity and lung damage was evaluated. Sputum from CF patients induced little lung hemorrhage when instilled intranasally in C57BL/6 mice. However, sputum treated in vitro by the addition of 1 mg/ml bovine DNase I showed increased neutrophil elastase activity (7.97 ± 1.56 versus 3.91 ± 0.62 μ M, p < 0.01) and induced marked lung hemorrhage in mice (bronchoalveolar lavage fluid hemoglobin = 192.8 ± 40.7 versus 44.5 ± 12.0 μ g/ml, p < 0.01). These effects were not observed with DNase I alone in phosphate buffer and were suppressed by the human neutrophil elastase inhibitor methoxysuccinyl-alanyl-alanyl-prolyl-valine-chloromethylketone (MeOSAAPV-CMK). In vivo administration of 2.5 mg aerosolized recombinant human DNase I to patients with CF resulted in a 2.2-fold increase of sputum elastase activity within 1 h of treatment. Elastase levels returned to pre-rhDNase therapy levels 24 h after aerosol treatment. Sputum collected 1 h after rhDNase on 4 separate days from two of six patients in which elastase levels were highest, induced lung hemorrhage when instilled intranasally in mice. We conclude that DNase I therapy of patients with cystic fibrosis can acutely increase the elastase activity of sputum and also its potential to induce hemorrhage in the murine lung.