tbuckley/cabot-search huggingface dataset:
ERS/ESTS clinical guidelines on fitness for radical therapy in lung cancer patients (surgery and chemo-radiotherapy)
Authors: A. Brunelli, A. Charloux, C. T. Bolliger, G. Rocco, J-P. Sculier, G. Varela, M. Licker, M. K. Ferguson, C. Faivre-Finn, R. M. Huber, E. M. Clini, T. Win, D. De Ruysscher, L. Goldman
Journal: European Respiratory Journal (2009)

A collaboration of multidisciplinary experts on the functional evaluation of lung cancer patients has been facilitated by the European Respiratory Society (ERS) and the European Society of Thoracic Surgery (ESTS), in order to draw up recommendations and provide clinicians with clear, up-to-date guidelines on fitness for surgery and chemo-radiotherapy. The subject was divided into different topics, which were then assigned to at least two experts. The authors searched the literature according to their own strategies, with no central literature review being performed. The draft reports written by the experts on each topic were reviewed, discussed and voted on by the entire expert panel. The evidence supporting each recommendation was summarised, and graded as described by the Scottish Intercollegiate Guidelines Network Grading Review Group. Clinical practice guidelines were generated and finalized in a functional algorithm for risk stratification of the lung resection candidates, emphasising cardiological evaluation, forced expiratory volume in 1 s, systematic carbon monoxide lung diffusion capacity and exercise testing. Contrary to lung resection, for which the scientific evidences are more robust, we were unable to recommend any specific test, cut-off value, or algorithm before chemo-radiotherapy due to the lack of data. We recommend that lung cancer patients should be managed in specialised settings by multidisciplinary teams.
Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation
Authors: Yoshihiko Ichikawa, Mohsen Ghanefar, Marina Bayeva, Rongxue Wu, Arineh Khechaduri, Sathyamangla V. Naga Prasad, R. Kannan Mutharasan, Tejaswitha Jairaj Naik, Hossein Ardehali
Journal: Journal of Clinical Investigation (2014)

Doxorubicin is an effective anticancer drug with known cardiotoxic side effects. It has been hypothesized that doxorubicin-dependent cardiotoxicity occurs through ROS production and possibly cellular iron accumulation. Here, we found that cardiotoxicity develops through the preferential accumulation of iron inside the mitochondria following doxorubicin treatment. In isolated cardiomyocytes, doxorubicin became concentrated in the mitochondria and increased both mitochondrial iron and cellular ROS levels. Overexpression of ABCB8, a mitochondrial protein that facilitates iron export, in vitro and in the hearts of transgenic mice decreased mitochondrial iron and cellular ROS and protected against doxorubicin-induced cardiomyopathy. Dexrazoxane, a drug that attenuates doxorubicin-induced cardiotoxicity, decreased mitochondrial iron levels and reversed doxorubicin-induced cardiac damage. Finally, hearts from patients with doxorubicin-induced cardiomyopathy had markedly higher mitochondrial iron levels than hearts from patients with other types of cardiomyopathies or normal cardiac function. These results suggest that the cardiotoxic effects of doxorubicin develop from mitochondrial iron accumulation and that reducing mitochondrial iron levels protects against doxorubicin-induced cardiomyopathy.
Molecular coevolution among cryptically simple expansion segments of eukaryotic 26S/28S rRNAs.
Authors: J M Hancock, G A Dover
Journal: Molecular Biology and Evolution (1988)

The set of "expansion segments" of any eukaryotic 26S/28S ribosomal RNA (rRNA) gene is responsible for the bulk of the difference in length between the prokaryotic 23S rRNA gene and the eukaryotic 26S/28S rRNA gene. The expansion segments are also responsible for interspecific fluctuations in length during eukaryotic evolution. They show a consistent bias in base composition in any species; for example, they are AT rich in Drosophila melanogaster and GC rich in vertebrate species. Dot-matrix comparisons of sets of expansion segments reveal high similarities between members of a set within any 28S rRNA gene of a species, in contrast to the little or spurious similarity that exists between sets of expansion segments from distantly related species. Similarities among members of a set of expansion segments within any 28S rRNA gene cannot be accounted for by their base-compositional bias alone. In contrast, no significant similarity exists within a set of "core" segments (regions between expansion segments) of any 28S rRNA gene, although core segments are conserved between species. The set of expansion segments of a 26S/28S gene is coevolving as a unit in each species, at the same time as the family of 28S rRNA genes, as a whole, is undergoing continual homogenization, making all sets of expansion segments from all ribosomal DNA (rDNA) arrays in a species similar in sequence. Analysis of DNA simplicity of 26S/28S rRNA genes shows a direct correlation between significantly high relative simplicity factors (RSFs) and sequence similarity among a set of expansion segments. A similar correlation exists between RSF values, overall rDNA lengths, and the lengths of individual expansion segments. Such correlations suggest that most length fluctuations reflect the gain and loss of simple sequence motifs by slippage-like mechanisms. We discuss the molecular coevolution of expansion segments, which takes place against a background of slippage-like and unequal crossing-over mechanisms of turnover that are responsible for the accumulation of interspecific differences in rDNA sequences.
5′ CArG degeneracy in smooth muscle α-actin is required for injury-induced gene suppression in vivo
Authors: Jennifer A. Hendrix, Brian R. Wamhoff, Oliver G. McDonald, Sanjay Sinha, Tadashi Yoshida, Gary K. Owens
Journal: Journal of Clinical Investigation (2005)

CC(A/T)6GG–dependent (CArG-dependent) and serum response factor–dependent (SRF-dependent) mechanisms are required for gene expression in smooth muscle cells (SMCs). However, an unusual feature of many SMC-selective promoter CArG elements is that they contain a conserved single G or C substitution in their central A/T-rich region, which reduces binding affinity for ubiquitously expressed SRF. We hypothesized that this CArG degeneracy contributes to cell-specific expression of smooth muscle α-actin in vivo, since substitution of c-fos consensus CArGs for the degenerate CArGs resulted in relaxed specificity in cultured cells. Surprisingly, our present results show that these substitutions have no effect on smooth muscle–specific transgene expression during normal development and maturation in transgenic mice. However, these substitutions significantly attenuated injury-induced downregulation of the mutant transgene under conditions where SRF expression was increased but expression of myocardin, a smooth muscle–selective SRF coactivator, was decreased. Finally, chromatin immunoprecipitation analyses, together with cell culture studies, suggested that myocardin selectively enhanced SRF binding to degenerate versus consensus CArG elements. Our results indicate that reductions in myocardin expression and the degeneracy of CArG elements within smooth muscle promoters play a key role in phenotypic switching of smooth muscle cells in vivo, as well as in mediating responses of CArG-dependent smooth muscle genes and growth regulatory genes under conditions in which these 2 classes of genes are differentially expressed.
Combined Ultrasmall Superparamagnetic Particles of Iron Oxide–Enhanced and Diffusion-weighted Magnetic Resonance Imaging Facilitates Detection of Metastases in Normal-sized Pelvic Lymph Nodes of Patients with Bladder and Prostate Cancer
Authors: Frédéric D. Birkhäuser, Urs E. Studer, Johannes M. Froehlich, Maria Triantafyllou, Lauren J. Bains, Giuseppe Petralia, Peter Vermathen, Achim Fleischmann, Harriet C. Thoeny
Journal: European Urology (2013)
Tumor Antigen–Targeted, Monoclonal Antibody–Based Immunotherapy: Clinical Response, Cellular Immunity, and Immunoescape
Authors: Robert L. Ferris, Elizabeth M. Jaffee, Soldano Ferrone
Journal: Journal of Clinical Oncology (2010)

Tumor antigen (TA) -targeted monoclonal antibodies (mAb), rituximab, trastuzumab, and cetuximab, are clinically effective for some advanced malignancies, especially in conjunction with chemotherapy and/or radiotherapy. However, these results are only seen in a subset (20% to 30%) of patients. We discuss the immunologic mechanism(s) underlying these clinical findings and their potential role in the variability in patients' clinical response.
GENETIC ENGINEERING AND GENE ANALYSIS
Authors: F.M. Pope
Journal: British Journal of Dermatology (1983)

Journal Article GENETIC ENGINEERING AND GENE ANALYSIS Get access F.M. Pope F.M. Pope Dermatology Research Group, M.R.C. Clinical Research Centre, Harrow, Middlesex Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 109, Issue 4, 1 October 1983, Pages 465–472, https://doi.org/10.1111/j.1365-2133.1983.tb04622.x Published: 01 October 1983
Heterogeneity of autoreactive T cell clones specific for the E2 component of the pyruvate dehydrogenase complex in primary biliary cirrhosis.
Authors: J Van de Water, A Ansari, T Prindiville, R L Coppel, N Ricalton, B L Kotzin, S Liu, T E Roche, S M Krams, S Munoz, M E Gershwin
Journal: The Journal of Experimental Medicine (1995)

The extraordinary specificity of bile duct destruction in primary biliary cirrhosis (PBC) and the presence of T cell infiltrates in the portal tracts have suggested that biliary epithelial cells are the targets of an autoimmune response. The immunodominant antimitochondrial response in patients with PBC is directed against the E2 component of pyruvate dehydrogenase (PDC-E2). Hitherto, there have only been limited reports on the characterization and V beta usage of PDC-E2-specific cloned T cell lines. In this study, we examined peripheral blood mononuclear cells (PBMC) for their reactivity to the entire PDC complex as well as to the E1- and E2-specific components. We also examined the phenotype, lymphokine profile, and V beta usage of PDC-specific T cell clones isolated from cellular infiltrates from the livers of PBC patients. We report that PBMC from 16/19 patients with PBC, but not 12 control patients, respond to the PDC-E2 subunit. Interestingly, this response was directed to the inner and/or the outer lipoyl domains, despite the serologic observation that the autoantibody response is directed predominantly to the inner lipoyl domain. Additionally, lymphokine analysis of interleukin (IL) 2/IL-4/interferon gamma production from individual liver-derived autoantigen-specific T cell clones suggests that both T helper cell Th1- and Th2-like clones are present in the liver. Moreover, there was considerable heterogeneity in the T cell receptor for antigen (TCR) V beta usage of these antigen-specific autoreactive T cell clones. This is in contrast to murine studies in which animals are induced to develop autoimmunity by specific immunization and have an extremely limited T cell V beta repertoire. Thus, our data suggest that in human organ-specific autoimmune diseases, such as PBC, the TCR V beta repertoire is heterogenous.
Down but Not Out
Authors: Pankaj Sharma, Paul Bentley
Journal: Circulation Research (2010)

T he success of genome-wide association studies (GWAS) has breathed new life into our genetic understanding of common cardiovascular diseases such as heart disease, 1 stroke, 2 and hypertension. 3These combined diseases account for the largest mortality rates in the West, surpassing cancer and infectious diseases.The strategies deployed in dissecting out their genetic etiology have ranged from candidate gene-, family-based linkage studies to GWAS.Now that whole genome approaches are beginning to bear fruit, should we consign the oft-used candidate gene-based association study to history?Certainly it appears that, at least for stroke, our success rate for correctly identifying candidate genes has steadily and consistently diminished over the years. 4This probably is because most likely candidates for stroke have derived from ischemic heart disease genes with the assumption that both disease processes have similar pathophysiologies.As most of these candidates have been surveyed 5 and our etiologic understanding of these conditions becomes increasingly tested, GWAS, not being hampered by such limitations and requiring no a priori hypothesis, lends itself open to identifying novel gene loci and therapeutic targets.However, the article by Ding et al in this issue of Circulation Research 6 serves to remind us that an intelligent genetic approach to common diseases still has mileage.Synthesis of the vasodilator NO is suppressed by the amino acid asymmetrical dimethylarginine (ADMA), which displaces L-arginine, the natural substrate for NO synthesis. 7onsequently, factors that elevate plasma ADMA levels will secondarily reduce NO synthesis.Given that NO exerts significant protection against a wide variety of vascular disorders, ranging from stroke, atherosclerosis, hypertension, hyperlipidemia, diabetes, and renal failure, genetic variants that modify ADMA levels would themselves be predicted to act as risk factors for cardiovascular disease.One such candidate, tested by the authors here, is the gene coding for the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which hydrolyzes ADMA to L-citrulline and dimethylamines.Two isoforms of DDAH (1 and 2) are known to
MECHANISMS IN THE SUPPRESSION OF DELAYED HYPERSENSITIVITY IN THE GUINEA PIG BY 6-MERCAPTOPURINE
Authors: S. Michael Phillips, Burton Zweiman
Journal: The Journal of Experimental Medicine (1973)

The mechanism of suppression, of delayed hypersensitivity to tuberculoprotein by 6-mercaptopurine (6-MP) was studied in guinea pigs. Under the conditions of the protocol, suppression of tuberculin delayed skin test reactivity was not associated with a significantly altered end-organ response to mediators of permeability. No significant alteration of in vivo lymphoid activity, as measured by reconstitution studies, was found. In addition, lymphoid cells from 6-MP-treated animals reacted in a fashion similar to those of placebo-treated animals with respect to (a) antigen-induced lymphocyte proliferation, (b) antigen-induced liberation of macrophage inhibitory factor activity, (c) direct inhibition by antigen of peritoneal exudate cell migration. Conversely, suppression was seen in levels of blood monocytes and in vitro function of macrophages from 6-MP-treated animals in several respects: (a) adherence to glass, (b) migratory rate, (c) phagocytic capacity. Therefore, it would appear that a ma]or mechanism of 6-MP-induced suppression of delayed hypersensitivity is through its action on effector cells.
Observations on THE CONTROL OF TRACHOMA
Authors: N. B. Harman
Journal: BMJ (1930)

TRACHOMA is practically extinct in England.It is still prevalent in some parts of the British Empire.It is rampant in some Eastern countries.Trachoma was at one time common in England.The coniditions that have con- duced to its virtual extinction are worth investigation.They may point tlle way to measures calculated to secure a similar result elsewhere.The necessity for control of a disease depends upon the measure of the damage done by it.To obtain this measure there would be needed a census of the eye conditionis of the population.This is maanifestly impossible.But we can fairly compare figures drawn from the examination of sec- tions of thie polulation.These, although not national mraps, Imiay be fair average samples.Hospital figures cannot be considered such samples, for they are obtained from selected portions of the population.The most desir- able figures arm to be obtained from the schools, and from the examination of recruits for military service.
Characterisation of mucosal lymphoid aggregates in ulcerative colitis: immune cell phenotype and TcR-gamma delta expression
Authors: M M-W Yeung
Journal: Gut (2000)

<h3>BACKGROUND AND AIMS</h3> A histopathological feature considered indicative of ulcerative colitis (UC) is the so-called basal lymphoid aggregates. Their relevance in the pathogenesis of UC is, however, unknown. We have performed a comprehensive analysis of the immune cells in these aggregates most likely corresponding to the lymphoid follicular hyperplasia also described in other colitides. <h3>METHODS</h3> Resection specimens of UC and normal colon were analysed by immunomorphometry, immunoflow cytometry, and immunoelectron microscopy, using a large panel of monoclonal antibodies. <h3>RESULTS</h3> (1) In all cases of UC, colonic lamina propria contained numerous basal aggregates composed of lymphocytes, follicular dendritic cells, and CD80/B7.1 positive dendritic cells. (2) CD4<sup>+</sup>CD28<sup>−</sup>αβ T cells and B cells were the dominant cell types in the aggregates. (3) The aggregates contained a large fraction of cells that are normally associated with the epithelium: that is, γδ T cells (11 (7)%) and α<sub>E</sub>β<sub>7</sub><sup>+</sup>cells (26 (13)%). The γδ T cells used Vδ1 and were CD4<sup>−</sup>CD8<sup>−</sup>. Immunoelectron microscopy analysis demonstrated TcR-γδ internalisation and surface downregulation, indicating that the γδ T cells were activated and engaged in the disease process. (4) One third of cells in the aggregates expressed the antiapoptotic protein bcl-2. <h3>CONCLUSIONS</h3> Basal lymphoid aggregates in UC colon are a consequence of anomalous lymphoid follicular hyperplasia, characterised by abnormal follicular architecture and unusual cell immunophenotypes. The aggregates increase in size with severity of disease, and contain large numbers of apoptosis resistant cells and activated mucosal γδ T cells. The latter probably colonise the aggregates as an immunoregulatory response to stressed lymphocytes or as a substitute for defective T helper cells in B cell activation. γδ T cells in the aggregates may be characteristic of UC.
Levels of Prostaglandin E Metabolite, the Major Urinary Metabolite of Prostaglandin E2, Are Increased in Smokers
Authors: Neil D. Gross, Jay O. Boyle, Jason D. Morrow, Myles K. Williams, Chaya S. Moskowitz, Kotha Subbaramaiah, Andrew J. Dannenberg, Anna J. Duffield-Lillico
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Increased levels of cyclooxygenase-2 and prostaglandin E2 (PGE2) have been observed in tobacco-related malignancies of the upper aerodigestive tract. Moreover, exposure to tobacco smoke can stimulate the synthesis of PGE2. Recent evidence suggests that urinary PGE metabolite (PGE-M) can be used as an index of systemic PGE2 production. In this study, we investigated whether levels of urinary PGE-M were increased in smokers and in patients with head and neck squamous cell carcinoma (HNSCC). Experimental Design: Fifty-eight HNSCC cases and 29 age- and gender-matched healthy controls were prospectively enrolled in the study. A detailed smoking history and single void urine specimen were obtained from each participant. Levels of urinary PGE-M were quantified in a blinded fashion using mass spectrometry and compared with smoking history and tumor status. Results: Adjusted for case-control matching, median urinary PGE-M levels were significantly higher in ever smokers (15.7 ng/mg creatinine) compared with never smokers (9.9 ng/mg creatinine) for the entire study population (n = 87, P = 0.005). Concentrations of urinary PGE-M were nearly doubled in ever smokers (15.2 ng/mg creatinine) versus never smokers (7.8 ng/mg creatinine) among healthy controls (P = 0.001). Higher PGE-M levels were observed in current versus former smokers and in those with greater pack-year exposure. A significant difference in amounts of PGE-M was not observed in patients with HNSCC versus healthy controls. Conclusions: Increased levels of urinary PGE-M were observed in smokers. Urinary PGE-M may have use as a noninvasive biomarker of the effects of tobacco smoke exposure.
Proliferative Glomerulonephritis with Monoclonal IgG Deposits
Authors: Samih H. Nasr, Anjali Satoskar, Glen S. Markowitz, Anthony M. Valeri, Gerald B. Appel, Michael B. Stokes, Tibor Nadasdy, Vivette D. D'Agati
Journal: Journal of the American Society of Nephrology (2009)

Dysproteinemias that result in monoclonal glomerular deposits of IgG are relatively uncommon. Here, we report the largest series of proliferative glomerulonephritis with monoclonal IgG deposits, a form of renal involvement by monoclonal gammopathy that mimics immune-complex glomerulonephritis. We retrospectively identified 37 patients, most of whom were white (81%), female (62%), or older than 50 yr (65%). At presentation, 49% had nephrotic syndrome, 68% had renal insufficiency, and 77% had hematuria. In 30% of the patients, we identified a monoclonal serum protein with the same heavy- and light-chain isotypes as the glomerular deposits (mostly IgG1 or IgG2), but only one patient had myeloma. Histologic patterns were predominantly membranoproliferative (57%) or endocapillary proliferative (35%) with membranous features. Electron microscopy revealed granular, nonorganized deposits, and immunofluorescence demonstrated glomerular deposits that stained for a single light-chain isotype and a single heavy-chain subtype, most commonly IgG3κ (53%). During an average of 30.3 mo of follow-up for 32 patients with available data, 38% had complete or partial recovery, 38% had persistent renal dysfunction, and 22% progressed to ESRD. Correlates of ESRD on univariate analysis were higher creatinine at biopsy, percentage of glomerulosclerosis, and degree of interstitial fibrosis but not immunomodulatory treatment or presence of a monoclonal spike. On multivariate analysis, higher percentage of glomerulosclerosis was the only independent predictor of ESRD. Only one patient lacking a monoclonal spike at presentation subsequently developed a monoclonal spike and no patient with a monoclonal spike at presentation subsequently developed a hematologic malignancy. We conclude that proliferative glomerulonephritis with monoclonal IgG deposits does not seem to be a precursor of myeloma in the vast majority of patients.
Regulation of rat heme oxygenase-1 expression by interleukin-6 via the Jak/STAT pathway in hepatocytes
Authors: Kyrylo Tron, Anatoly Samoylenko, Gernot Musikowski, Fritz Kobe, Stephan Immenschuh, Fred Schaper, Giuliano Ramadori, Thomas Kietzmann
Journal: Journal of Hepatology (2006)