tbuckley/cabot-search huggingface dataset:
MicroRNA-494 Downregulates KIT and Inhibits Gastrointestinal Stromal Tumor Cell Proliferation
Authors: Won Kyu Kim, Misun Park, Young-Kook Kim, You Kwon Tae, Han-Kwang Yang, Jae Myun Lee, Hoguen Kim
Journal: Clinical Cancer Research (2011)

Gain-of-function mutations and KIT overexpression are well-known tumorigenesis mechanisms in gastrointestinal stromal tumors (GIST). This study aimed to discover microRNAs (miRNA) that target KIT and reveal the relationship between the discovered miRNAs and KIT expression in GISTs.Fresh-frozen GISTs from 31 patients were used to confirm the relationship between miR-494 and KIT expression using quantitative reverse transcription-PCR to assess miR-494 expression levels and Western blotting to assess KIT protein expression levels. A luciferase assay was conducted for the target evaluation. The functional effects of miR-494 on GIST882 cells (GIST cell line with activating KIT mutation) were validated by a cell proliferation assay and fluoresce-activated cell sorting analysis.An inverse relationship was found between the expression levels of miR-494 and KIT in GISTs (r = -0.490, P = 0.005). The direct targeting of KIT by miR-494 was shown by the reduction in KIT expression after miR-494 overexpression and the increase in KIT expression after inhibiting endogenous miR-494 expression. We showed that miR-494 regulates KIT by binding two different seed match sites. Induced miR-494 overexpression in GIST882 reduced the expression of downstream molecules in KIT signaling transduction pathways, including phospho-AKT and phospho-STAT3. Finally, miR-494 overexpression provoked apoptosis and inhibited GIST cell growth, which were accompanied by changes in G(1) and S phase content.Our findings indicate that miR-494 is a negative regulator of KIT in GISTs and overexpressing miR-494 in GISTs may be a promising approach to GIST treatment.
Tumorigenicity and lysis by natural killers.
Authors: J L Collins, P Q Patek, M Cohn
Journal: The Journal of Experimental Medicine (1981)

Detailed analysis of the natural killer (NK) activity directed at nontumorigenic cell lines and their transformed tumorigenic derivatives has revealed a paradox. On the one hand, a correlation has been found between the tumorigenic potential of chemically transformed fibroblast cell lines and their sensitivity to NK cells in vitro. Nontransformed cells (N-type cell lines) and cells tumorigenic in normal mice (C-type cell lines) are resistant to NK-mediated lysis. In contrast, cell lines that are tumorigenic in ATxFL mice (these mice are very low in NK activity), but not in normal mice (I-type cell lines) are sensitive to NK-mediated lysis. These findings support the concept that NK activity is involved in host surveillance against tumors. On the other hand, NK-resistant fibroblasts, whether taken directly form animals or derived as tumorigenic or nontumorigenic cell lines, compete with NK-sensitive target cells to inhibit their lysis by NK effectors. Not only are both NK-sensitive and -resistant cells recognized by NK effectors but both receive lytic signals from NK effector cells. Target cell resistance is a result of a protein synthesis-dependent mechanism that prevents lysis such that in the presence of inhibitors of protein synthesis all fibroblasts tested are NK sensitive. Those fibroblasts that are normally sensitive to NK-mediated lysis must be deficient in their ability to produce or respond to this counterlytic mechanism. These findings are in contrast with the general findings when lymphoid cells are studied as NK targets where sensitivity appears to be a result of recognition by NK effectors. Because our findings show that transformed and normal cells express the same recognition determinants, in order for NK activity to play an important in vivo role in tumor surveillance, a mechanism must operate to permit NK effectors to find their targets in vivo. In the absence of a special discrimination mechanism, the killing of NK-sensitive transformants that arise autochronously would be less than optimal as a consequence of competition by the normal, NK-resistant, cells.
Superiority of [68Ga]-DOTATATE PET/CT to Other Functional Imaging Modalities in the Localization of <i>SDHB</i>-Associated Metastatic Pheochromocytoma and Paraganglioma
Authors: Ingo Janssen, Elise M. Blanchet, Karen Adams, Clara C. Chen, Corina M. Millo, Peter Herscovitch, David Taieb, Electron Kebebew, Hendrik Lehnert, Antonio T. Fojo, Karel Pacak
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Patients with succinate dehydrogenase subunit B(SDHB) mutation–related pheochromocytoma/paraganglioma (PHEO/PGL) are at a higher risk for metastatic disease than other hereditary PHEOs/PGLs. Current therapeutic approaches are limited, but the best outcomes are based on the early and proper detection of as many lesions as possible. Because PHEOs/PGLs overexpress somatostatin receptor 2 (SSTR2), the goal of our study was to assess the clinical utility of [68Ga]-DOTA(0)-Tyr(3)-octreotate ([68Ga]-DOTATATE) positron emission tomography/computed tomography (PET/CT) and to evaluate its diagnostic utility in comparison with the currently recommended functional imaging modalities [18F]-fluorodopamine ([18F]-FDA), [18F]-fluorodihydroxyphenylalanine ([18F]-FDOPA), [18F]-fluoro-2-deoxy-d-glucose ([18F]- FDG) PET/CT as well as CT/MRI. Experimental Design: [68Ga]-DOTATATE PET/CT was prospectively performed in 17 patients with SDHB-related metastatic PHEOs/PGLs. All patients also underwent [18F]-FDG PET/CT and CT/MRI, with 16 of the 17 patients also receiving [18F]-FDOPA and [18F]-FDA PET/CT scans. Detection rates of metastatic lesions were compared between all these functional imaging studies. A composite synthesis of all used functional and anatomical imaging studies served as the imaging comparator. Results: [68Ga]-DOTATATE PET/CT demonstrated a lesion-based detection rate of 98.6% [95% confidence interval (CI), 96.5%–99.5%], [18F]-FDG, [18F]-FDOPA, [18F]-FDA PET/CT, and CT/MRI showed detection rates of 85.8% (CI, 81.3%–89.4%; P &amp;lt; 0.01), 61.4% (CI, 55.6%–66.9%; P &amp;lt; 0.01), 51.9% (CI, 46.1%–57.7%; P &amp;lt; 0.01), and 84.8% (CI, 80.0%–88.5%; P &amp;lt; 0.01), respectively. Conclusions: [68Ga]-DOTATATE PET/CT showed a significantly superior detection rate to all other functional and anatomical imaging modalities and may represent the preferred future imaging modality in the evaluation of SDHB-related metastatic PHEO/PGL. Clin Cancer Res; 21(17); 3888–95. ©2015 AACR. See related commentary by Hofman and Hicks, p. 3815
STUDIES ON THE CHEMICAL NATURE OF THE SUBSTANCE INDUCING TRANSFORMATION OF PNEUMOCOCCAL TYPES
Authors: Oswald T. Avery, Colin M. MacLeod, Maclyn McCarty
Journal: The Journal of Experimental Medicine (1944)

1. From Type III pneumococci a biologically active fraction has been isolated in highly purified form which in exceedingly minute amounts is capable under appropriate cultural conditions of inducing the transformation of unencapsulated R variants of Pneumococcus Type II into fully encapsulated cells of the same specific type as that of the heat-killed microorganisms from which the inducing material was recovered. 2. Methods for the isolation and purification of the active transforming material are described. 3. The data obtained by chemical, enzymatic, and serological analyses together with the results of preliminary studies by electrophoresis, ultracentrifugation, and ultraviolet spectroscopy indicate that, within the limits of the methods, the active fraction contains no demonstrable protein, unbound lipid, or serologically reactive polysaccharide and consists principally, if not solely, of a highly polymerized, viscous form of desoxyribonucleic acid. 4. Evidence is presented that the chemically induced alterations in cellular structure and function are predictable, type-specific, and transmissible in series. The various hypotheses that have been advanced concerning the nature of these changes are reviewed.
Reprogramming Metabolism with Metformin Improves Tumor Oxygenation and Radiotherapy Response
Authors: Vanessa E. Zannella, Alan Dal Pra, Hala Muaddi, Trevor D. McKee, Shawn Stapleton, Jenna Sykes, Rachel Glicksman, Selim Chaib, Paul Zamiara, Michael Milosevic, Bradly G. Wouters, Robert G. Bristow, Marianne Koritzinsky
Journal: Clinical Cancer Research (2013)

Tumor hypoxia is a negative prognostic factor in multiple cancers, due in part to its role in causing resistance to radiotherapy. Hypoxia arises in tumor regions distal to blood vessels as oxygen is consumed by more proximal tumor cells. Reducing the rate of oxygen consumption is therefore a potential strategy to reduce tumor hypoxia. We hypothesized that the anti-diabetic drug metformin, which reduces oxygen consumption through inhibition of mitochondrial complex I, would improve radiation response by increasing tumor oxygenation.Tumor hypoxia was measured in xenografts before and after metformin treatment using 2-nitroimidazole hypoxia markers quantified by immunohistochemistry (IHC), flow cytometry, and positron emission tomography (PET) imaging. Radiation response was determined by tumor growth delay and clonogenic survival in xenografts with and without administration of metformin. The impact of metformin use on outcome was assessed in 504 patients with localized prostate cancer treated with curative-intent, image-guided radiotherapy (IGRT) from 1996 to 2012. Three-year biochemical relapse-free rates were assessed using the Kaplan-Meier method.Metformin treatment significantly improved tumor oxygenation in two xenograft models as measured by IHC, flow cytometry, and PET imaging. Metformin also led to improved radiotherapy responses when mice were administered metformin immediately before irradiation. Clinically, metformin use was associated with an independent and significant decrease in early biochemical relapse rates (P = 0.0106).Our data demonstrate that metformin can improve tumor oxygenation and response to radiotherapy. Our study suggests that metformin may represent an effective and inexpensive means to improve radiotherapy outcome with an optimal therapeutic ratio.
DOCK5 functions as a key signaling adaptor that links FcεRI signals to microtubule dynamics during mast cell degranulation
Authors: Kana Ogawa, Yoshihiko Tanaka, Takehito Uruno, Xuefeng Duan, Yosuke Harada, Fumiyuki Sanematsu, Kazuhiko Yamamura, Masao Terasawa, Akihiko Nishikimi, Jean-François Côté, Yoshinori Fukui
Journal: The Journal of Experimental Medicine (2014)

Mast cells play a key role in the induction of anaphylaxis, a life-threatening IgE-dependent allergic reaction, by secreting chemical mediators that are stored in secretory granules. Degranulation of mast cells is triggered by aggregation of the high-affinity IgE receptor, FcεRI, and involves dynamic rearrangement of microtubules. Although much is known about proximal signals downstream of FcεRI, the distal signaling events controlling microtubule dynamics remain elusive. Here we report that DOCK5, an atypical guanine nucleotide exchange factor (GEF) for Rac, is essential for mast cell degranulation. As such, we found that DOCK5-deficient mice exhibit resistance to systemic and cutaneous anaphylaxis. The Rac GEF activity of DOCK5 is surprisingly not required for mast cell degranulation. Instead, DOCK5 associated with Nck2 and Akt to regulate microtubule dynamics through phosphorylation and inactivation of GSK3β. When DOCK5–Nck2–Akt interactions were disrupted, microtubule formation and degranulation response were severely impaired. Our results thus identify DOCK5 as a key signaling adaptor that orchestrates remodeling of the microtubule network essential for mast cell degranulation.
Growth Inhibition of Normal or Drug-Treated Lymphoma Cells in Lethally Irradiated Mice2
Authors: C. Riccardi, M. C. Fioretti, A. Giampietri, P. Puccetti, A. Goldin, E. Bonmassar
Journal: JNCI Journal of the National Cancer Institute (1978)

Journal Article Growth Inhibition of Normal or Drug-Treated Lymphoma Cells in Lethally Irradiated Mice Get access C. Riccardi, C. Riccardi Search for other works by this author on: Oxford Academic PubMed Google Scholar M. C. Fioretti, M. C. Fioretti Search for other works by this author on: Oxford Academic PubMed Google Scholar A. Giampietri, A. Giampietri Search for other works by this author on: Oxford Academic PubMed Google Scholar P. Puccetti, P. Puccetti Search for other works by this author on: Oxford Academic PubMed Google Scholar A. Goldin, A. Goldin Search for other works by this author on: Oxford Academic PubMed Google Scholar E. Bonmassar E. Bonmassar Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 60, Issue 5, May 1978, Pages 1083–1090, https://doi.org/10.1093/jnci/60.5.1083 Published: 01 May 1978 Article history Received: 09 August 1977 Accepted: 14 November 1977 Published: 01 May 1978
Protein Kinase Activation by Warm And Cold Hypoxia- Reoxygenation in Primary-Cultured Rat Hepatocytes–JNK1/SAPK1 Involvement in Apoptosis
Authors: Dominique Crenesse, Jean Gugenheim, Joelle Hornoy, Karine Tornieri, Marina Laurens, Beatrice Cambien, Gaelle Lenegrate, Rafaele Cursio, Georges De Souza, Patrick Auberger, Catherine Heurteaux, Bernard Rossi, Annie Schmid-Alliana
Journal: Hepatology (2000)

Ischemia-reperfusion procedures induced severe hepatic damages owing to different processes related to hypoxia and reoxygenation (H/R) phases, including the consecutive oxygen free radical (OFR) release. Stress-activated protein kinases (SAPKs) could be activated by extracellular stimuli. The aim of this study was to show whether H/R stress conditions could stimulate these kinases, and especially c-jun-N-terminal kinase (JNK(1)/SAPK(1)), to reveal a potential role of JNK(1)/SAPK(1) in the control of hepatocyte apoptosis. Primary cultured rat hepatocytes, isolated from other liver cells and blood flow, were subjected to warm and cold hypoxia-reoxygenation phases mimicking surgical and transplant conditions. The activation status of SAPKs was evaluated by immunoprecipitation or Western-blotting experiments, whereas apoptosis was assessed by measuring caspase activation and internucleosomal DNA fragmentation in vitro and by TUNEL reaction, in vivo. Hypoxia, and especially hypoxia-reoxygenation, significantly increased JNK(1)/SAPK(1) activation in cultured hepatocytes. Either in warm or cold conditions, OFR scavengers (N-Acetylcystein, Di-Phenyleneiodonium, Deferoxamine) decreased this stimulation. Warm ischemia-reperfusion also led to JNK activation. Hypoxia and especially hypoxia-reoxygenation induced programmed cell death in vivo and in vitro. This last phenomenon was inhibited when hepatocytes were treated with SB 202190, which was described as a potent inhibitor of p38 and JNK activities. Altogether, these results confirmed that JNK(1)/SAPK(1) was activated during the hypoxia-reoxygenation process, and that this activity participated in the onset of the apoptosis program.
Expression of Natural Killer Receptor Alleles at Different Ly49 Loci Occurs Independently and Is Regulated by Major Histocompatibility Complex Class I Molecules
Authors: Dawn M. Tanamachi, Thomas Hanke, Hisao Takizawa, Amanda M. Jamieson, David H. Raulet
Journal: The Journal of Experimental Medicine (2001)

Ly49 receptor genes are expressed by subsets of natural killer (NK) cells in an overlapping fashion, accounting for the capacity of NK subsets to attack host cells that have selectively downregulated self–major histocompatibility complex (MHC) class I molecules. It was shown previously that most NK cells express only one or the other allele of a given Ly49 gene, while a smaller population expresses both alleles. However, the methods used to detect monoallelic and biallelic cells were nonquantitative. Here, new allele-specific antibodies were used to provide the first quantitative examination of biallelic and monoallelic expression of Ly49A and Ly49G2. The results demonstrate conclusively that most Ly49A+ and Ly49G2+ NK cells express the corresponding gene in a monoallelic fashion, with a smaller subset expressing both alleles. Unexpectedly, biallelic Ly49A+ NK cells were more numerous than predicted by completely independent allelic expression, suggesting some heterogeneity among NK progenitors in the potential to express a given Ly49 gene. The data also show that cells expressing one allele of Ly49G2 may express Ly49A from the same or opposite chromosome with equal likelihood, indicating that the expressed allele is chosen independently for different Ly49 genes. Finally, the data demonstrate that biallelic expression of Ly49A or Ly49G2 occurs least frequently in mice that express ligands for these receptors (H-2d mice), and most frequently in class I–deficient mice. Thus, biallelic expression of Ly49 genes is regulated by interactions of NK cell progenitors with MHC class I molecules.
Mitochondrial DNA G10398A Polymorphism and Invasive Breast Cancer in African-American Women
Authors: Jeffrey A. Canter, Asha R. Kallianpur, Fritz F. Parl, Robert C. Millikan
Journal: Cancer Research (2005)

Abstract Mitochondria generate oxygen-derived free radicals that damage mitochondrial DNA (mtDNA) as well as nuclear DNA and in turn promote carcinogenesis. The mtDNA G10398A polymorphism alters the structure of Complex I in the mitochondrial electron transport chain, an important site of free radical production. This polymorphism is associated with several neurodegenerative disorders. We hypothesized that the 10398A allele is also associated with breast cancer susceptibility. African mitochondria harbor the 10398A allele less frequently than Caucasian mitochondria, which predominantly carry this allele. Mitochondrial genotypes at this locus were therefore determined in two separate populations of African-American women with invasive breast cancer and in controls. A preliminary study at Vanderbilt University (48 cases, 54 controls) uncovered an association between the 10398A allele and invasive breast cancer in African-American women, [odds ratio (OR), 2.90; 95% confidence interval (95% CI), 0.61-18.3; P = 0.11]. We subsequently validated this finding in a large, population-based, case-control study of breast cancer, the Carolina Breast Cancer Study at the University of North Carolina (654 cases, 605 controls). African-American women in this study with the 10398A allele had a significantly increased risk of invasive breast cancer (OR, 1.60; 95% CI, 1.10-2.31; P = 0.013). The 10398A allele remained an independent risk factor after adjustment for other well-accepted breast cancer risk factors. No association was detectable in white women (879 cases, 760 controls; OR, 1.03; 95% CI, 0.81-1.31; P = 0.81). This study provides novel epidemiologic evidence that the mtDNA 10398A allele influences breast cancer susceptibility in African-American women. mtDNA polymorphisms may be underappreciated factors in breast carcinogenesis.
Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials
Authors: G. C. Machado, C. G. Maher, P. H. Ferreira, M. B. Pinheiro, C.-W. C. Lin, R. O. Day, A. J. McLachlan, M. L. Ferreira
Journal: BMJ (2015)

<b>Objective</b> To investigate the efficacy and safety of paracetamol (acetaminophen) in the management of spinal pain and osteoarthritis of the hip or knee. <b>Design</b> Systematic review and meta-analysis. <b>Data sources</b> Medline, Embase, AMED, CINAHL, Web of Science, LILACS, International Pharmaceutical Abstracts, and Cochrane Central Register of Controlled Trials from inception to December 2014. <b>Eligibility criteria for selecting studies</b> Randomised controlled trials comparing the efficacy and safety of paracetamol with placebo for spinal pain (neck or low back pain) and osteoarthritis of the hip or knee. <b>Data extraction</b> Two independent reviewers extracted data on pain, disability, and quality of life. Secondary outcomes were adverse effects, patient adherence, and use of rescue medication. Pain and disability scores were converted to a scale of 0 (no pain or disability) to 100 (worst possible pain or disability). We calculated weighted mean differences or risk ratios and 95% confidence intervals using a random effects model. The Cochrane Collaboration's tool was used for assessing risk of bias, and the GRADE approach was used to evaluate the quality of evidence and summarise conclusions. <b>Results</b> 12 reports (13 randomised trials) were included. There was "high quality" evidence that paracetamol is ineffective for reducing pain intensity (weighted mean difference −0.5, 95% confidence interval −2.9 to 1.9) and disability (0.4, −1.7 to 2.5) or improving quality of life (0.4, −0.9 to 1.7) in the short term in people with low back pain. For hip or knee osteoarthritis there was "high quality" evidence that paracetamol provides a significant, although not clinically important, effect on pain (−3.7, −5.5 to −1.9) and disability (−2.9, −4.9 to −0.9) in the short term. The number of patients reporting any adverse event (risk ratio 1.0, 95% confidence interval 0.9 to 1.1), any serious adverse event (1.2, 0.7 to 2.1), or withdrawn from the study because of adverse events (1.2, 0.9 to 1.5) was similar in the paracetamol and placebo groups. Patient adherence to treatment (1.0, 0.9 to 1.1) and use of rescue medication (0.7, 0.4 to 1.3) was also similar between groups. "High quality" evidence showed that patients taking paracetamol are nearly four times more likely to have abnormal results on liver function tests (3.8, 1.9 to 7.4), but the clinical importance of this effect is uncertain. <b>Conclusions</b> Paracetamol is ineffective in the treatment of low back pain and provides minimal short term benefit for people with osteoarthritis. These results support the reconsideration of recommendations to use paracetamol for patients with low back pain and osteoarthritis of the hip or knee in clinical practice guidelines. <b>Systematic review registration</b> PROSPERO registration number CRD42013006367.
Increased Uptake of<i>BRCA1/2</i>Genetic Testing Among African American Women With a Recent Diagnosis of Breast Cancer
Authors: Lisa R. Susswein, Cécile Skrzynia, Leslie A. Lange, Jessica K. Booker, Mark L. Graham, James P. Evans
Journal: Journal of Clinical Oncology (2007)

Purpose Studies suggest that African American women are less likely to pursue BRCA1/2 genetic testing than white women. However, such studies are often confounded by unequal access to care. Methods Data from 132 African American and 636 white women, obtained from a clinical database at the University of North Carolina (Chapel Hill, NC) between 1998 and 2005, were analyzed to assess BRCA1/2 genetic testing uptake. Importantly, the clinical setting minimized barriers of both cost and access. Race and time of new breast cancer diagnosis (recent v &gt; 1 year before genetic evaluation) were assessed for association with BRCA1/2 testing uptake using multivariable logistic regression models. Results Both race (P = .0082) and a recent diagnosis of breast cancer (P = .014) were independently associated with testing uptake. African American women had a lower estimated odds of pursuing testing than white women (odds ratio [OR], 0.54; 95%CI, 0.34 to 0.85), and women with a recent diagnosis had a higher OR than those with a remote diagnosis (OR, 1.58; 95% CI, 1.10 to 2.29). In a race-stratified analysis, there was no statistical evidence for association between recent status and testing uptake in the larger white stratum (OR, 1.38, P = .13) while there was for the smaller African American sample (OR, 2.77, P = .018). The test of interaction between race and remote status was not significant (P = .15). Conclusion African American race was associated with an overall decreased uptake of BRCA1/2 genetic testing, even when barriers of ascertainment and cost were minimized. However, among African American women, a recent diagnosis of breast cancer was associated with substantially increased uptake of testing.