tbuckley/cabot-search huggingface dataset:
Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4.
Authors: N G Jacobson, S J Szabo, R M Weber-Nordt, Z Zhong, R D Schreiber, J E Darnell, K M Murphy
Journal: The Journal of Experimental Medicine (1995)

Interleukin 12 (IL-12) initiates the differentiation of naive CD4+ T cells to T helper type 1 (Th1) cells critical for resistance to intracellular pathogens such as Leishmania major. To explore the basis of IL-12 action, we analyzed induction of nuclear factors in Th1 cells. IL-12 selectively induced nuclear DNA-binding complexes that contained Stat3 and Stat4, recently cloned members of the family of signal transducers and activators of transcription (STATs). While Stat3 participates in signaling for several other cytokines, Stat4 was not previously known to participate in the signaling pathway for any natural ligand. The selective activation of Stat4 provides a basis for unique actions of IL-12 on Th1 development. Thus, this study presents the first identification of the early events in IL-12 signaling in T cells and of ligand activation of Stat4.
Abstract 11396: Discordant Grading of Aortic Stenosis Severity: Echocardiographic Predictors of Survival Benefit From Aortic Valve Replacement
Authors: Maxime Berthelot-Richer, Philippe Pibarot, Romain Capoulade, Jean G. Dumesnil, Abdelaziz Dahou, Florent Le Ven, Christophe Thebault, Marie-Annick Clavel
Journal: Circulation (2013)

Background: Discordant findings between aortic valve area (AVA≤1.0cm2) and mean gradient (MG≥40mmHg) raise uncertainty regarding the actual severity of the aortic stenosis (AS). Some studies sugges...
Functional Growth in Tissue-Engineered Living, Vascular Grafts
Authors: Simon P. Hoerstrup, Ian Cummings MRCS, Mario Lachat, Frederick J. Schoen, Rolf Jenni, Sebastian Leschka, Stefan Neuenschwander, Dörthe Schmidt, Anita Mol, Christina Günter, Mathias Gössi, Michele Genoni, Gregor Zund
Journal: Circulation (2006)

Background— Living autologous vascular grafts with the capacity for regeneration and growth may overcome the limitations of contemporary artificial prostheses. Particularly in congenital cardiovascular surgery, there is an unmet medical need for growing replacement materials. Here we investigate growth capacity of tissue-engineered living pulmonary arteries in a growing lamb model. Methods and Results— Vascular grafts fabricated from biodegradable scaffolds (ID 18±l mm) were sequentially seeded with vascular cells. The seeded constructs were grown in vitro for 21days using biomimetic conditions. Thereafter, these tissue-engineered vascular grafts (TEVGs) were surgically implanted as main pulmonary artery replacements in 14 lambs using cardiopulmonary bypass and followed up for ≤100 weeks. The animals more than doubled their body weight during the 2-year period. The TEVG showed good functional performance demonstrated by regular echocardiography at 20, 50, 80, and 100 weeks and computed tomography-angiography. In particular, there was no evidence of thrombus, calcification, stenosis, suture dehiscence, or aneurysm. There was a significant increase in diameter by 30% and length by 45%. Histology showed tissue formation reminiscent of native artery. Biochemical analysis revealed cellularity and proteoglycans and increased collagen contents in all of the groups, analogous to those of native vessels. The mechanical profiles of the TEVG showed stronger but less elastic tissue properties than native pulmonary arteries. Conclusions— This study provides evidence of growth in living, functional pulmonary arteries engineered from vascular cells in a full growth animal model.
Proficient Global Nucleotide Excision Repair in Human Keratinocytes but not in Fibroblasts Deficient in p53
Authors: Bridget E. Ferguson, Dennis H. Oh
Journal: Cancer Research (2005)

Abstract The p53 tumor suppressor protein is important for many cellular responses to DNA damage in mammalian cells, but its role in regulating DNA repair in human keratinocytes is undefined. We compared the nucleotide excision repair (NER) response of human fibroblasts and keratinocytes deficient in p53. Fibroblasts expressing human papillomavirus 16 E6 oncoprotein had impaired repair of UV radiation–induced cyclobutane pyrimidine dimers in association with reduced levels of p53 and XPC, which is involved in DNA damage recognition. In contrast, keratinocytes expressing E6 alone or concurrently with the E7 oncoprotein, while possessing reduced levels of p53 but normal levels of XPC, continued to repair pyrimidine dimers as efficiently as control cells with normal p53 levels. Despite preservation of DNA repair, E6 and E6/E7 keratinocytes were hypersensitive to UV radiation. E6 fibroblasts exhibited markedly reduced basal and induced levels of mRNA encoding DDB2, another protein implicated in early events in global NER. In contrast, E6 or E6/E7 keratinocytes possessed basal DDB2 mRNA levels that were not significantly altered relative to control cells, although little induction occurred following UV radiation. Intact global NER was also confirmed in SCC25 cells possessing inactivating mutations in p53 as well as in cells treated with pifithrin-α, a chemical inhibitor of p53 that decreased sensitivity of cells to UV radiation. Collectively, these results indicate that human keratinocytes, unlike fibroblasts, do not require p53 to maintain basal global NER activity, but p53 may still be important in mediating inducible responses following DNA damage.
Evolution and Diversification of the Organellar Release Factor Family
Authors: Isabel Duarte, Sander B. Nabuurs, Ramiro Magno, Martijn Huynen
Journal: Molecular Biology and Evolution (2012)

Translation termination is accomplished by proteins of the Class I release factor family (RF) that recognize stop codons and catalyze the ribosomal release of the newly synthesized peptide. Bacteria have two canonical RFs: RF1 recognizes UAA and UAG, RF2 recognizes UAA and UGA. Despite that these two release factor proteins are sufficient for de facto translation termination, the eukaryotic organellar RF protein family, which has evolved from bacterial release factors, has expanded considerably, comprising multiple subfamilies, most of which have not been functionally characterized or formally classified. Here, we integrate multiple sources of information to analyze the remarkable differentiation of the RF family among organelles. We document the origin, phylogenetic distribution and sequence structure features of the mitochondrial and plastidial release factors: mtRF1a, mtRF1, mtRF2a, mtRF2b, mtRF2c, ICT1, C12orf65, pRF1, and pRF2, and review published relevant experimental data. The canonical release factors (mtRF1a, mtRF2a, pRF1, and pRF2) and ICT1 are derived from bacterial ancestors, whereas the others have resulted from gene duplications of another release factor. These new RF family members have all lost one or more specific motifs relevant for bona fide release factor function but are mostly targeted to the same organelle as their ancestor. We also characterize the subset of canonical release factor proteins that bear nonclassical PxT/SPF tripeptide motifs and provide a molecular-model-based rationale for their retained ability to recognize stop codons. Finally, we analyze the coevolution of canonical RFs with the organellar genetic code. Although the RF presence in an organelle and its stop codon usage tend to coevolve, we find three taxa that encode an RF2 without using UGA stop codons, and one reverse scenario, where mamiellales green algae use UGA stop codons in their mitochondria without having a mitochondrial type RF2. For the latter, we put forward a "stop-codon reinvention" hypothesis that involves the retargeting of the plastid release factor to the mitochondrion.
Phase I-II Study of Gemcitabine and Carboplatin in Stage IIIB-IV Non–Small-Cell Lung Cancer
Authors: Rosario Vincenzo Iaffaioli, Anna Tortoriello, Gaetano Facchini, Francesco Caponigro, Maria Gentile, Nicola Marzano, Adriano Gravina, Paolo Dimitri, Giuseppina Costagliola, Alessandro Ferraro, Giovanni Ferrante, Valeria De Marino, Alfonso Illiano
Journal: Journal of Clinical Oncology (1999)

PURPOSE: Platinum-based chemotherapy currently represents standard treatment for advanced non–small-cell lung cancer. Gemcitabine is one of the most interesting agents currently in use in advanced non–small-cell lung cancer, and high response rates have been reported when it is administered in combination with cisplatin. The aim of the present study was to evaluate the combination of gemcitabine and carboplatin in a phase I-II study. PATIENTS AND METHODS: Chemotherapy-naive patients with stage IIIB-IV non–small-cell lung cancer received carboplatin at area under the concentration-time curve (AUC) 5 mg/mL/min and gemcitabine at an initial dose of 800 mg/m 2 , subsequently escalated by 100 mg/m 2 per step. Gemcitabine was administered on days 1 and 8 and carboplatin on day 8 of the 28-day cycle. Dose escalation proceeded up to dose-limiting toxicity (DLT), which was defined as grade 4 neutropenia or thrombocytopenia or grade 3 nonhematologic toxicity. RESULTS: Neutropenia was DLT, inasmuch as it occurred in three of five patients receiving gemcitabine 1,200 mg/m 2 . Nonhematologic toxicities were mild. Gemcitabine 1,100 mg/m 2 plus carboplatin AUC 5 was recommended for phase II studies. An objective response was observed in 13 (50%) of 26 patients, including four complete responses (15%) and nine partial responses (35%). Median duration of response was 13 months (range, 3 to 23 months). Median overall survival was 16 months (range, 3 to 26 months). CONCLUSION: The combination of gemcitabine and carboplatin is well tolerated and active. Neutropenia was DLT. The observed activity matches that observable in cisplatin-gemcitabine studies, whereas duration of response and survival are even higher. A phase II trial is under way.
Dependence of Initiation of an Innocent Bystander Cytotoxicity Reaction on the Association of Viral Antigens and Tumor Cell Membranes in Mice<xref ref-type="fn" rid="FN1">2</xref>
Authors: D M Lopez, P F Lopez, W P Parks, R D Paul
Journal: JNCI Journal of the National Cancer Institute (1986)

In chemically induced mouse mammary tumors in BALB/c mice, no murine mammary tumor virus (MuMTV) antigens could be detected in the tumor cell membranes. In contrast, in mammary tumors of spontaneous appearance in BALB/cfC3H mice neonatally infected with MuMTV, viral antigens could be detected by immunofluorescence. Specific activation of immune spleen lymphocytes in vitro by homologous tumor cell membrane preparations resulted in an innocent bystander cytotoxicity reaction in BALB/c mice bearing either the chemical- or virus-induced mammary tumors. Non-tumor bearers did not respond in this reaction. The cytotoxicity effector cell was a nylon-adherent Thy 1.2+, Lyt 1+, Lyt 2+ lymphocyte. Induction of the reaction in the chemically induced mammary tumor bearers was related to tumor-associated antigens, but in the mice with MuMTV-induced tumors, it was possible that all responses were solely due to viral antigens. Biochemical analyses using immunoprecipitation techniques indicated that the major external glycoprotein of MuMTV (gp52) was present in the tumor cell membrane preparations. Preincubation of the cell membranes of virus-induced tumors with anti-MuMTV completely blocked the capacity of this preparation to induce the cytotoxicity. Preabsorption of the anti-MuMTV with purified MuMTV removed all the blocking activity of these sera, indicating that the antigenic determinants recognized were of viral origin. However, purified MuMTV failed by itself to elicit the innocent bystander cytotoxicity. This observation indicates that an association with membranes was necessary for the viral antigens to initiate and/or effect this cell-mediated immune reaction.
Prognostic Value of Energy Loss Index in Asymptomatic Aortic Stenosis
Authors: Edda Bahlmann, Eva Gerdts, Dana Cramariuc, Christa Gohlke-Baerwolf, Christoph A. Nienaber, Kristian Wachtell, Reinhard Seifert, John B. Chambers, Karl Heinz Kuck, Simon Ray
Journal: Circulation (2013)

Background— Aortic valve area index adjusted for pressure recovery (energy loss index [ELI]) has been suggested as a more accurate measure of aortic stenosis (AS) severity, but its prognostic value has not been determined in a prospective study. Methods and Results— The relation between baseline ELI and rate of aortic valve events and combined total mortality and hospitalization for heart failure resulting from the progression of AS was assessed by multivariate Cox regression and reclassification analysis in 1563 patients with initial asymptomatic AS in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. During 4.3 years follow-up, a total of 498 aortic valve events and 181 combined total mortalities and hospitalizations for heart failure caused by the progression of AS occurred. In Cox regression analyses, 1-cm 2 /m 2 lower baseline ELI predicted a 2-fold higher risk both for aortic valve events and for combined total mortality and hospitalization for heart failure independently of baseline peak aortic jet velocity or mean aortic gradient and independently of aortic root size (all P &lt;0.05). In reclassification analysis, ELI improved the prediction of aortic valve events by 13% (95% confidence interval, 5–19), whereas the prediction of combined total mortality and hospitalization for heart failure resulting from the progression of AS did not improve significantly. Conclusions— In asymptomatic AS patients without known atherosclerotic disease or diabetes mellitus, ELI provides independent and additional prognostic information to that derived from conventional measures of AS severity, suggesting that ELI should be measured in such patients. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00092677.
Gene-Environment Interaction in Psychological Traits and Disorders
Authors: Danielle M. Dick
Journal: Annual Review of Clinical Psychology (2011)

There has been an explosion of interest in studying gene-environment interactions (GxE) as they relate to the development of psychopathology. In this article, I review different methodologies to study gene-environment interaction, providing an overview of methods from animal and human studies and illustrations of gene-environment interactions detected using these various methodologies. Gene-environment interaction studies that examine genetic influences as modeled latently (e.g., from family, twin, and adoption studies) are covered, as well as studies of measured genotypes. Importantly, the explosion of interest in gene-environment interactions has raised a number of challenges, including difficulties with differentiating various types of interactions, power, and the scaling of environmental measures, which have profound implications for detecting gene-environment interactions. Taking research on gene-environment interactions to the next level will necessitate close collaborations between psychologists and geneticists so that each field can take advantage of the knowledge base of the other.
Adalimumab in acute sciatica reduces the long-term need for surgery: a 3-year follow-up of a randomised double-blind placebo-controlled trial
Authors: S Genevay, A Finckh, P Zufferey, S Viatte, F Balagué, C Gabay
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Introduction</h3> Two subcutaneous injections of adalimumab in severe acute sciatica significantly reduced the number of back operations in a short-term randomised controlled clinical trial. <h3>Objective</h3> To determine in a 3-year follow-up study whether the short-term benefit of adalimumab in sciatica is sustained over a longer period of time. <h3>Methods</h3> The primary outcome of this analysis was incident discectomy. Three years after randomisation, information on surgery could be retrieved in 56/61 patients (92%).A multivariate Cox proportional hazard models, adjusted for potential confounders, was used to determine factors predisposing to surgery. <h3>Results</h3> Twenty-three (41%) patients had back surgery within 3 years, 8/29 (28%) in the adalimumab group and 15/27 (56%) in the placebo group, p=0.04. Adalimumab injections reduced the need for back surgery by 61% (HR)=0.39 (95% CI 0.17 to 0.92). In a multivariate model, treatment with a tumour necrosis factor-α antagonist remained the strongest protective factor (HR=0.17, p=0.002). Other significant predictors of surgery were a good correlation between symptoms and MRI findings (HR=11.6, p=0.04), baseline intensity of leg pain (HR=1.3, p=0.06), intensity of back pain (HR=1.4, p=0.03) and duration of sickness leave (HR=1.01 per day, p=0.03). <h3>Conclusion</h3> A short course of adalimumab in patients with severe acute sciatica significantly reduces the need for back surgery.
Left ventricular myocardial edema. Lymph flow, interstitial fibrosis, and cardiac function.
Authors: G A Laine, S J Allen
Journal: Circulation Research (1991)

We hypothesized that both acute and chronic accumulation of myocardial interstitial edema (extravascular fluid [EVF]) would compromise cardiac function. We also postulated that excess fluid within the myocardial interstitial space would potentiate interstitial fibrosis, thus further compromising function. Dogs were divided into three groups: 1) control, 2) chronic pulmonary hypertensive with right heart failure, and 3) chronic arterial hypertensive. The quantity of EVF, expressed as the unitless blood-free (wet weight-dry weight)/dry weight ratio, and interstitial fibrosis (collagen content) were determined and correlated with cardiac function at baseline and after acute elevation of coronary venous pressure and reduction of cardiac lymph flow. Control EVF was 2.90 +/- 0.20 (mean +/- SD), which increased to 3.45 +/- 0.16 after acute (3-hour) elevation of coronary sinus pressure. This EVF significantly compromised cardiac function. The EVF in chronically hypertensive dogs and in dogs with chronic right heart pressure elevations was 3.50 +/- 0.30 and 3.50 +/- 0.08, respectively. End-diastolic left ventricular interstitial fluid pressure increased from a control value of 14.9 +/- 3.1 (at EVF = 2.9) to 24.8 +/- 3.7 (at EVF = 3.5). An EVF of 3.5 produced approximately 30% reduction of the heart's ability to maintain cardiac output at a left atrial pressure of 15 mm Hg. The compromised function in these chronic models is exacerbated after acute elevation of coronary venous pressure and reduction of cardiac lymph flow. Collagen levels were elevated by at least 20% in the chronic hypertensive dogs and in the nonhypertrophied left ventricles of dogs with chronic right heart pressure elevation.(ABSTRACT TRUNCATED AT 250 WORDS)
The BTS and our 25th anniversary
Authors: S. Edwards
Journal: Thorax (2007)

An organisation “fit for purpose”

As the British Thoracic Society (BTS) comes to the end of its 25th anniversary year, several articles in this issue of Thorax have been commissioned to provide accounts of some of the important developments in respiratory medicine that have impacted on practice.

As well as the developments described in these articles, it is a suitable time to reflect on the changes that have taken place in the management and governance of the Society’s affairs. These have provided a strong frame, a sturdy heart and a healthy set of bellows to fuel the drive and enthusiasm of all those colleagues over the last 25 years who have contributed to the Society’s achievements. There have been several key events since Dr Martin MacNicol and Dr Harry Gribbin led a highly significant “think tank” in the early 1990s. This gave shape and structure to the Society’s constitution and set up the Standing Committee structure which has remained in …
Targeting EGFR and HER-2 receptor tyrosine kinases for cancer drug discovery and development
Authors: Shantaram Kamath, John K. Buolamwini
Journal: Medicinal Research Reviews (2006)

Conventional anticancer therapy using cytotoxic drugs lacks selectivity and is prone to toxicity and drug resistance. Anticancer therapies targeting aberrant growth factor receptor signaling are gaining interest. The erbB receptor family belongs to the type I, the receptor tyrosine kinases class, and comprises EGFR, HER-2, HER-3, and HER-4. It has been targeted for solid tumor therapy, including breast, ovarian, colon, head-and-neck, and non-small-cell lung cancers. This review summarizes structural aspects of this class of growth factor receptors, their oncogenic expression, and various pharmacological interventions including biological products and small molecules that inhibit these enzymes. We have also discussed various mutations that occur in EGFR and their consequences on anticancer therapy. © 2006 Wiley Periodicals, Inc. Med Res Rev, 26, No. 5, 569–594, 2006
Readthrough of nonsense mutation W822X in the SCN5A gene can effectively restore expression of cardiac Na+ channels
Authors: Siyong Teng, Lizhi Gao, Vesa Paajanen, Jielin Pu, Zheng Fan
Journal: Cardiovascular Research (2009)

Nonsense mutations in the SCN5A gene result in truncated, non-functional derivatives of the cardiac Na+ channel and thus cause arrhythmias. Studies of other genes suggest that pathogenic phenotypes of nonsense mutations may be alleviated by enhancing readthrough, which enables ribosomes to ignore premature termination codons and produce full-length proteins. Thus, we studied the functional restoration of nonsense-mutated SCN5A.HEK293 cells were transfected with SCN5A cDNA or its mutant carrying W822X, a nonsense mutation associated with Brugada syndrome and sudden cardiac death. The effects of readthrough-enhancing reagents on Na+ channel expression and function were examined in the transfected cells. W822X robustly reduced Na+ current, decreasing maximal Na+ current to <3% of the wild-type level, and inhibited the expression of full-length Na+ channels. When readthrough was enhanced by either reducing translational fidelity with aminoglycosides or decreasing translation termination efficiency with small-interfering RNA against eukaryotic release factor eRF3a, Na+ current of the mutant was restored to approximately 30% of the wild-type level; western blot and immunochemical staining analyses showed the increased expression of full-length channels. When the wild-type and mutant cDNAs were co-transfected, readthrough-enhancing reagents increased Na+ current from 56% to 74% of the wild-type level. Analysis of Na+ channel kinetics showed that the channels expressed from the mutant cDNA under readthrough-enhancing conditions retained the functions of wild-type channels.Readthrough-enhancing reagents can effectively suppress SCN5A nonsense mutations and may restore the expression of full-length Na+ channels with normal functions, which might prevent sudden cardiac death in mutation carriers.