tbuckley/cabot-search huggingface dataset:
Resveratrol Inhibits Drug-Induced Apoptosis in Human Leukemia Cells by Creating an Intracellular Milieu Nonpermissive for Death Execution
Authors: Kashif Adil Ahmad, Marie-Veronique Clement, Ismail Muhamad Hanif, Shazib Pervaiz
Journal: Cancer Research (2004)

Abstract Efficient apoptotic signaling is a function of a permissive intracellular milieu created by a decrease in the ratio of superoxide to hydrogen peroxide and cytosolic acidification. Resveratrol (RSV) triggers apoptosis in some systems and inhibits the death signal in others. In this regard, the inhibitory effect on hydrogen peroxide-induced apoptosis is attributed to its antioxidant property. We provide evidence that exposure of human leukemia cells to low concentrations of RSV (4–8 μm) inhibits caspase activation, DNA fragmentation, and translocation of cytochrome c induced by hydrogen peroxide or anticancer drugs C2, vincristine, and daunorubicin. Interestingly, at these concentrations, RSV induces an increase in intracellular superoxide and inhibits drug-induced acidification. Blocking the activation of NADPH oxidase complex neutralized RSV-induced inhibition of apoptosis. Furthermore, our results implicate intracellular hydrogen peroxide as a common effector mechanism in drug-induced apoptosis that is inhibited by preincubation with RSV. Interestingly, decreasing intracellular superoxide with the NADPH oxidase inhibitor diphenyliodonium reversed the inhibitory effect of RSV on drug-induced hydrogen peroxide production. These data show that low concentrations of RSV inhibit death signaling in human leukemia cells via NADPH oxidase-dependent elevation of intracellular superoxide that blocks mitochondrial hydrogen peroxide production, thereby resulting in an intracellular environment nonconducive for death execution.
Interleukin-6–dependent gene expression profiles in multiple myeloma INA-6 cells reveal a Bcl-2 family–independent survival pathway closely associated with Stat3 activation
Authors: Katja Brocke-Heidrich, Antje K. Kretzschmar, Gabriele Pfeifer, Christian Henze, Dennis Löffler, Dirk Koczan, Hans-Jürgen Thiesen, Renate Burger, Martin Gramatzki, Friedemann Horn
Journal: Blood (2003)
Designed Ankyrin Repeat Proteins (DARPins): Binding Proteins for Research, Diagnostics, and Therapy
Authors: Andreas Plückthun
Journal: The Annual Review of Pharmacology and Toxicology (2011)

Designed ankyrin repeat proteins (DARPins) can recognize targets with specificities and affinities that equal or surpass those of antibodies, but because of their robustness and extreme stability, they allow a multitude of more advanced formats and applications. This review highlights recent advances in DARPin design, illustrates their properties, and gives some examples of their use. In research, they have been established as intracellular, real-time sensors of protein conformations and as crystallization chaperones. For future therapies, DARPins have been developed by advanced, structure-based protein engineering to selectively induce apoptosis in tumors by uncoupling surface receptors from their signaling cascades. They have also been used successfully for retargeting viruses. In ongoing clinical trials, DARPins have shown good safety and efficacy in macular degeneration diseases. These developments all ultimately exploit the high stability, solubility, and aggregation resistance of these molecules, permitting a wide range of conjugates and fusions to be produced and purified.
THE GENETICS OF OSTEOPOROSIS: Vitamin D Receptor Polymorphisms
Authors: Richard J. Wood, James C. Fleet
Journal: Annual Review of Nutrition (1998)

▪ Abstract Osteoporosis is a metabolic bone disease characterized by low bone mass and deterioration of bone tissue that leads to bone fragility and an increase in fracture risk. It is a disease with a complex etiology that includes genetic and environmental contributors. Environmental factors that influence bone density include dietary factors—such as intakes of calcium, alcohol, and caffeine—and lifestyle factors—such as exercise and smoking. Ethnic differences in the propensity to nontraumatic bone fracture suggest that genetic factors are important. Recently, common allelic variations in the vitamin D receptor gene have been found to be associated with bone mineral density in racially diverse population groups, as well as in prepubertal girls, young adult and postmenopausal women, and men. However, many studies have not been able to find this association. Additional approaches, such as sib-pair analysis, will probably be necessary in the future to identify the important genetic determinants of osteoporosis.
Haplotype analysis of congenital nephrotic syndrome of the Finnish type in non-Finnish families.
Authors: M Männikkö, U Lenkkeri, C E Kashtan, M Kestilä, C Holmberg, K Tryggvason
Journal: Journal of the American Society of Nephrology (1996)

Congenital nephrotic syndrome of the Finnish type (CNF) has an estimated incidence of 1 in 8000 newborns in the genetically isolated population of Finland. Although the disease is most common in Finland, it occurs throughout the world in families without known Finnish origin. In the past, these authors recently localized the CNF gene to the chromosome 19q13.1 region and observed strong linkage disequilibrium to the genetic markers D19S610, D19S608, D19S224, and D19S220 in Finnish families. In these Finnish families, four main CNF haplotype categories have been observed. In the study presented here, haplotype analysis was applied to several non-Finnish CNF families to determine whether the same genetic locus is involved in these families. The results of the haplotype analysis suggest linkage to the 19q13.1 chromosomal region. It was also observed that, in most cases, alleles typically found on CNF chromosomes of Finnish families are also found on CNF chromosomes of non-Finnish families from North America and Europe. In these families, the strongest association was found with marker D19S608. These findings suggest that Finnish and many non-Finnish CNF cases share the same disease locus.
Human keratinocytes produce but do not process pro-interleukin-1 (IL-1) beta. Different strategies of IL-1 production and processing in monocytes and keratinocytes.
Authors: H Mizutani, R Black, T S Kupper
Journal: Journal of Clinical Investigation (1991)

Keratinocytes comprise the majority of cells in the epidermis, the interleukin-1 rich layer of tissue contiguous with the outside world. Keratinocytes produce IL-1 alpha and beta mRNA in vitro, but only IL-1 alpha biological activity has been identified in keratinocyte cultures. In contrast, monocytes secrete biological activities attributable to both species of IL-1. Using several monoclonal antibodies to IL-1 beta, significant amounts of IL-1 beta protein could be found in keratinocyte cultures; all of this immunoreactive IL-1 beta was in the 31-kD form. This latent cytokine has been shown to bind inefficiently to the IL-1 receptor and to be (in relative terms) biologically inactive. Chymotrypsin cleaves 31-kD IL-1 beta at Tyr 113-Val 114, generating an 18-kD IL-1 species with activity equivalent to the authentic mature IL-1 beta (NH2-terminal Ala 117). Treatment of 31-kD keratinocyte IL-1 beta with chymotrypsin also generated an 18-kD molecule and significant IL-1 activity. Monocytes contain an IL-1 convertase enzyme that cleaves the IL-1 beta promolecule at Ala 117. We demonstrate here that keratinocytes do not contain such an IL-1 convertase activity, nor do they contain any activity capable of productively processing 31-kD IL-1 beta into a biologically active form. These data suggest that keratinocytes (and other non-bone marrow-derived cells) produce IL-1 beta in an inactive form that can be processed only after leaving the cell.
Increased quantity of tumor-infiltrating FOXP3-positive regulatory T cells is an independent predictor for improved clinical outcome in extranodal NK/T-cell lymphoma
Authors: W.Y. Kim, Y.K. Jeon, T.M. Kim, J.E. Kim, Y.A. Kim, S.-H. Lee, D.-W. Kim, D.S. Heo, C.-W. Kim
Journal: Annals of Oncology (2009)
Selective p38MAPK isoform expression and activation in antineutrophil cytoplasmatic antibody-associated crescentic glomerulonephritis: role of p38MAPK 
Authors: K Polzer, A Soleiman, W Baum, R Axmann, J Distler, K Redlich, A Kilian, G Kronke, G Schett, J Zwerina
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objective:</h3> Crescentic glomerulonephritis (crGN) is a frequent and life-threatening manifestation of antineutrophil cytoplasmatic antibody-associated vasculitis. Up-regulation of proinflammatory cytokines contributes to renal damage by activation of p38 mitogen-activated protein kinases (MAPKs). However, it is unclear which of the four p38MAPK isoforms are expressed, activated and hence of major importance in crGN. <h3>Methods:</h3> Kidney biopsies of patients with antineutrophil cytoplasmatic antibody-positive crGN and control samples were investigated for the expression and phosphorylation of p38MAPK isoforms and downstream target kinase MAPKAP2 by immunohistochemistry. Expression and functional activation of p38MAPK isoforms by TNF was also assessed in a human podocyte cell line by reverse transcription–polymerase chain reaction, immunoblotting and kinase array. <h3>Results:</h3> Strong expression of p38MAPKα, β and γ isoforms was found in glomerular podocytes and crescents. Infiltrating leucocytes showed predominant p38MAPKα expression. Activation of p38MAPK and its downstream mediator MAPKAP2 was found in crGN confined to glomerular podocytes, crescents and inflammatory infiltrates. Interestingly, corticosteroid treatment before kidney biopsy diminished p38MAPK activation in crGN. Activated p38MAPK co-localised with α, β and γ isoforms in podocytes and crescents, while leucocytes showed mainly p38MAPKα activation. In a human podocyte cell line mRNA and protein of all four p38MAPK isoforms was expressed but only p38MAPKα was activated upon challenge with TNF. <h3>Conclusions:</h3> This study shows selective p38MAPK isoform expression and activation in crGN. Podocytes and podocyte-induce crescent formation is the main source of p38MAPK activation in crGN. TNF is a potent and selective activator of the α-isoform in podocytes, which therefore appears as a main contributor to proinflammatory signalling in the glomerulum of crGN.
Pediatric high-grade astrocytomas: a distinct neuro-oncological paradigm
Authors: Noha Gerges, Adam M Fontebasso, Steffen Albrecht, Damien Faury, Nada Jabado
Journal: Genome Medicine (2013)

Brain tumors are the leading cause of cancer-related death in children. High-grade astrocytomas (HGAs), in particular, are lethal in children across all ages. Integrative genome-wide analyses of the tumor's genome, transcriptome and epigenome, using next-generation sequencing technologies and genome-wide DNA methylation arrays, have provided valuable breakthroughs in our understanding of the pathogenesis of HGAs across all ages. Recent profiling studies have provided insight into the epigenetic nature of gliomas in young adults and HGAs in children, particularly with the identification of recurrent gain-of-function driver mutations in the isocitrate dehydrogenase 1 and 2 genes (IDH1/2) and the epigenetic influence of their oncometabolite 2-hydroxyglutarate, as well as mutations in the histone 3 variant 3 gene (H3F3A) and loss-of-function mutations in the histone 3 lysine 36 trimethyltransferase gene (SETD2). Mutations in H3F3A result in amino acid substitutions at residues thought to directly (K27M) or indirectly (G34R/V) affect histone post-translational modifications, suggesting they have the capacity to affect the epigenome in a profound manner. Here, we review recent genomic studies, and discuss evidence supporting the molecular characterization of pediatric HGAs to complement traditional approaches, such as histology of resected tumors. We also describe newly identified molecular mechanisms and discuss putative therapeutic approaches for HGAs specific to pediatrics, highlighting the necessity for the evolution of HGA disease management approaches.
THE PREVENTION AND TREATMENT OF CHEMICAL PARKINSONISM WITH UK-738
Authors: SIDNEY COHEN
Journal: American Journal of Psychiatry (1961)

In the treatment of the long term psychotic patient who will require large amounts of phenothiazines, especially those with a piperazine ring in the side chain, consideration should be given to prevention of the EPS. UK-738 has satisfactorily suppressed these disturbing symptoms without adding undesirable side effects of its own. It has also proven to be an effective agent in the treatment of manifest chemical parkinsonism.
Androgen Receptor Promotes Hepatitis B Virus–Induced Hepatocarcinogenesis Through Modulation of Hepatitis B Virus RNA Transcription
Authors: Ming-Heng Wu, Wen-Lung Ma, Cheng-Lung Hsu, Yuh-Ling Chen, Jing-Hsiung James Ou, Charlotte Kathryn Ryan, Yao-Ching Hung, Shuyuan Yeh, Chawnshang Chang
Journal: Science Translational Medicine (2010)

Targeting androgen receptor may prevent hepatitis B virus–induced liver cancer.
Radiologic evaluation of emphysema in patients with chronic obstructive pulmonary disease. Chest radiography versus high resolution computed tomography.
Authors: M Miniati, E Filippi, F Falaschi, L Carrozzi, E N Milne, H D Sostman, M Pistolesi
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

To objectively reappraise the role of the chest radiograph (CXR) in the clinical assessment of emphysema, we compared a standardized reading of CXR with both a visual scoring and a quantitative analysis of high resolution computed tomography (HRCT) of the chest in 46 consecutive patients with chronic obstructive pulmonary disease (COPD) and fixed expiratory airflow limitation. CXR were scored for signs of overinflation and pulmonary vascular deficiency by three independent observers. HRCT scans were independently scored for extent of emphysema and for both severity and extent of emphysema. In 28 of 46 patients, inspiratory and expiratory HRCT scans were analyzed quantitatively by measuring the mean CT number in Hounsfield Units (HU) and the percentage of lung area with CT numbers < -900 HU. Quantitative CT data were compared with reference values obtained in seven normal nonsmokers. The CXR score of emphysema showed a highly significant interobserver reproducibility and correlated linearly (p < 0.001) with HRCT visual scores and quantitative data from both inspiratory and expiratory CT scan. CXR score correlated with functional indices of airflow obstruction, overinflation, and impaired lung diffusing capacity in a way comparable to that obtained by using qualitative and quantitative CT data. Patients with no signs of emphysema on CXR had mean expiratory CT numbers within normal range and a fraction of lung area with CT numbers < -900 HU on expiratory scan not exceeding 15% of total cross-sectional area. The latter value was consistently greater than 15% in patients with CXR score > 0.(ABSTRACT TRUNCATED AT 250 WORDS)
Aldehyde dehydrogenase 1A1—a new mediator of resistance to temozolomide in glioblastoma
Authors: Andrea Schäfer, Julian Teufel, Florian Ringel, Marcus Bettstetter, Ingrid Hoepner, Michael Rasper, Jens Gempt, Julia Koeritzer, Friederike Schmidt-Graf, Bernhard Meyer, Christoph P. Beier, Jürgen Schlegel
Journal: Neuro-Oncology (2012)

Implementation of chemotherapy with the drug temozolomide increased the overall survival of patients with glioblastoma multiforme (GBM; WHO grade IV), in particular when the O6-methylguanine DNA methyltransferase (MGMT) promoter is epigenetically silenced. Nevertheless, the prognosis remains poor, and relapse in GBM occurs regularly. This clinical behavior seems to be due to the existence of a therapy-resistant subpopulation of cells that induce tumor regrowth. The objective of this work was to analyze the role of aldehyde dehydrogenase (ALDH) 1A1 in mediating temozolomide resistance and its value as a predictor of clinical outcome in GBM patients. Nine GBM cell lines were treated with temozolomide alone or in combination with 4-diethylaminobenzaldehyde (DEAB), an inhibitor of ALDH1A1, or with ALDH1A1 short hairpin (sh)RNA. ALDH1A1 expression and MGMT status of 70 primary GBM patients were correlated with median survival. ALDH1A1 overexpression predicted temozolomide resistance in vitro. Sensitivity of ALDH1A1 positive/MGMT-positive cells to temozolomide could be restored by inhibition of ALDH1A1 by DEAB or by knockdown with shRNA, as indicated by increased cytotoxicity, reduced clonogenicity, and accumulation in the G2/M cell-cycle phase. The prognosis of patients with a high level of ALDH1A1 expression was poor compared with that of patients with low levels (P < .0001). ALDH1A1 is a new mediator for resistance of GBM to temozolomide and a reliable predictor of clinical outcome and may serve as a potential target to improve treatment of human GBM.
DOES THE TENDINOPATHIC PATELLAR TENDON NORMALISE, ACCORDING TO ULTRASOUND FINDINGS, AFTER TREATMENT WITH SCLEROSING INJECTIONS OR ARTHROSCOPIC SHAVING? A LONG TERM FOLLOW-UP (3–5 YEARS)
Authors: K Sunding, L Willberg, U Niklasson, S Werner
Journal: British Journal of Sports Medicine (2013)

Introduction Treatment of patellar tendinopathy/jumper's knee with ultrasound-guided sclerosing injections and arthroscopic shaving has shown good clinical results, but patients treated with the one-stage procedure arthroscopic shaving had a faster return to full activity, less pain and were more satisfied with the treatment result at follow-up approximately 1 year after end of treatment.1 There are studies suggesting that tendon structure in a tendinotic, chronic painful tendon does not sonographically normalise after successful treatment. However those results are based on a relatively short term follow up. Methods We have evaluated patellar tendons according to a routine ultrasound examination protocol for chronic painful patellar tendons/proximal patellar tendinopathy, 3 to 5 years after treatment with sclerosing injections (n=19) or arthroscopic shaving (n=25). Tendon thickness was measured and tendon structure and the amount of neovascularization was evaluated and scored, to be compared with corresponding values at baseline and at the 1 year follow-up. Self-reported pain during rest and patellar tendon loading activity, and patient satisfaction with the result of the treatment was registered on a visual analogue scale (VAS). Results At the 3–5 years follow-up, preliminary results showed that tendon structure seemed to improve, and the neovascularisation was reduced, in both groups. There was a trend towards a decrease in antero-posterior thickness of the proximal part of the patellar tendon in patients treated with arthroscopic shaving, but not for tendons treated with sclerosing injections. There were no differences in VAS score at rest and during activity between the two treatment groups or in VAS score for satisfaction with treatment. Discussion Treatment of patellar tendinopathy/jumper's knee with ultrasound and colour Doppler-guided sclerosing injections and arthroscopic shaving showed remaining good clinical results after 3–5 years for both methods. Treatment with sclerosing injections requires multiple injections with 6–8 weeks in between, but in the 3–5 years perspective seems to reach the same result in terms of ultrasound findings and self-reported pain (VAS) as treatment with the one-stage procedure arthroscopic shaving. This is in contrast to the results at 1 year follow-up where the surgical method showed better results in all evaluated variables. One remaining difference between the two treatments was that only the surgical method showed a decrease in antero-posterior thickness. In fact tendon thickness in the group treated with sclerosing injections were increased at the 1 year follow-up, while now 3–5 years after treatment the thickness seems to be back at the same level as at baseline, before treatment.
Complex Patterns of Altered MicroRNA Expression during the Adenoma-Adenocarcinoma Sequence for Microsatellite-Stable Colorectal Cancer
Authors: Angela N. Bartley, Hui Yao, Bedia A. Barkoh, Cristina Ivan, Bal M. Mishra, Asif Rashid, George A. Calin, Rajyalakshmi Luthra, Stanley R. Hamilton
Journal: Clinical Cancer Research (2011)

MicroRNAs are short noncoding RNAs that regulate gene expression and are over- or underexpressed in most tumors, including colorectal adenocarcinoma. MicroRNAs are potential biomarkers and therapeutic targets and agents, but limited information on microRNAome alterations during progression in the well-known adenoma-adenocarcinoma sequence is available to guide their usage.
Transcriptomic analysis of pathways regulated by toll-like receptor 4 in a murine model of chronic pulmonary inflammation and carcinogenesis
Authors: Alison K Bauer, Jennifer Fostel, Laura M Degraff, Elizabeth A Rondini, Christopher Walker, Sherry F Grissom, Julie Foley, Steven R Kleeberger
Journal: Molecular Cancer (2009)

Therapeutic strategies exist for human pulmonary neoplasia, however due to the heterogeneity of the disease, most are not very effective. The innate immunity gene, toll-like receptor 4 (TLR4), protects against chronic pulmonary inflammation and tumorigenesis in mice, but the mechanism is unclear. This study was designed to identify TLR4-mediated gene expression pathways that may be used as prognostic indicators of susceptibility to lung tumorigenesis in mice and provide insight into the mechanism. Whole lung mRNA was isolated from C.C3H-Tlr4Lps-d(BALBLps-d; Tlr4 mutant) and BALB/c (Tlr4 normal) mice following butylated hydroxytoluene (BHT)-treatment (four weekly ip. injections; 150-200 mg/kg/each; "promotion"). mRNA from micro-dissected tumors (adenomas) and adjacent uninvolved tissue from both strains were also compared 27 wks after a single carcinogen injection (3-methylcholanthrene (MCA), 10 μg/g; "control") or followed by BHT (6 weekly ip. injections; 125-200 mg/kg/each; "progression"). Bronchoalveolar lavage fluid was analyzed for inflammatory cell content and total protein determination, a marker of lung hyperpermeability; inflammation was also assessed using immunohistochemical staining for macrophages (F4/80) and lymphocytes (CD3) in mice bearing tumors (progression). During promotion, the majority of genes identified in the BALBLps-dcompared to BALB/c mice (P < 0.05) were involved in epithelial growth factor receptor (EGFR) signaling (e.g. epiregulin (Ereg)), secreted phosphoprotein 1(Spp1)), which can lead to cell growth and eventual tumor development. Inflammation was significantly higher in BALBLps-dcompared to BALB/c mice during progression, similar to the observed response during tumor promotion in these strains. Increases in genes involved in signaling through the EGFR pathway (e.g. Ereg, Spp1) were also observed during progression in addition to continued inflammation, chemotactic, and immune response gene expression in the BALBLps-dversus BALB/c mice (P < 0.05), which appears to provide more favorable conditions for cell growth and tumor development. In support of these findings, the BALB/c mice also had significantly reduced expression of many immune response and inflammatory genes in both the tumors and uninvolved tissue. This transcriptomic study determined the protective effect of TLR4 in lung carcinogenesis inhibition of multiple pathways including EGFR (e.g. Ereg), inflammatory response genes (e.g. Cxcl5), chemotaxis (e.g. Ccr1) and other cell proliferation genes (e.g. Arg1, Pthlh). Future studies will determine the utility of these pathways as indicators of immune system deficiencies and tumorigenesis.