tbuckley/cabot-search huggingface dataset:
Novel Oligoamine Analogues Inhibit Lysine-Specific Demethylase 1 and Induce Reexpression of Epigenetically Silenced Genes
Authors: Yi Huang, Tracy Murray Stewart, Yu Wu, Stephen B. Baylin, Laurence J. Marton, Brandy Perkins, Richard J. Jones, Patrick M. Woster, Robert A. Casero
Journal: Clinical Cancer Research (2009)

Abnormal DNA CpG island hypermethylation and transcriptionally repressive histone modifications are associated with the aberrant silencing of tumor suppressor genes. Lysine methylation is a dynamic, enzymatically controlled process. Lysine-specific demethylase 1 (LSD1) has recently been identified as a histone lysine demethylase. LSD1 specifically catalyzes demethylation of mono- and dimethyl-lysine 4 of histone 3 (H3K4), key positive chromatin marks associated with transcriptional activation. We hypothesized that a novel class of oligoamine analogues would effectively inhibit LSD1 and thus cause the reexpression of aberrantly silenced genes.Human colorectal cancer cells were treated with the oligoamines and changes in mono- and dimethyl-H3K4 and other chromatin marks were monitored. In addition, treated cells were evaluated for the reexpression of the aberrantly silenced secreted frizzled-related proteins (SFRP) Wnt signaling pathway antagonist genes. Finally, the effects of the LSD1 inhibitors were evaluated in an in vivo xenograft model.Treatment of HCT116 human colon adenocarcinoma cells in vitro resulted in increased H3K4 methylation and reexpression of silenced SFRP genes. This reexpression is also accompanied by a decrease in H3K9me2 repressive mark. Importantly, cotreatment with low doses of oligoamines and a DNA methyltransferase inhibitor highly induces the reexpression of the aberrantly silenced SFRP2 gene and results in significant inhibition of the growth of established tumors in a human colon tumor model in vivo.The use of LSD1-inhibiting oligoamine analogues in combination with DNA methyltransferase inhibitors represents a highly promising and novel approach for epigenetic therapy of cancer.
3rd International Ovarian Cancer Consensus Conference: outstanding issues for future consideration
Authors: G. Stuart, E. Avall-Lundqvist, A. du Bois, M. Bookman, D. Bowtell, M. Brady, A. Casado, A. Cervantes, E. Eisenhauer, M. Friedlaender, K. Fujiwara, S. Grenman, J.P. Guastalla, P. Harper, T. Hogberg, S. Kaye, H. Kitchener, G. Kristensen, R. Mannel, W. Meier, B. Miller, A. Oza, R. Ozols, M. Parmar, J. Pfisterer, A. Poveda, D. Provencher, E. Pujade-Lauraine, M. Quinn, M. Randall, J. Rochon, G. Rustin, S. Sagae, F. Stehman, E. Trimble, T. Thigpen, P. Vasey, I. Vergote, R. Verheijen, J. Vermorken, U. Wagner
Journal: Annals of Oncology (2005)
Serial Analysis of Gene Expression
Authors: Willmar D. Patino, Omar Y. Mian, Paul M. Hwang
Journal: Circulation Research (2002)

It has been 7 years since serial analysis of gene expression (SAGE) and microarray hybridization techniques were simultaneously introduced to allow the screening of thousands of expressed genes. Both techniques have stood up to the test of time as evidenced by their widespread use, and both have been used for studying cardiovascular diseases. SAGE has been used more extensively to study cancer cells, but it has also been used to examine gene expression in systems as divergent as rice seedlings, yeast, and Caenorhabditis elegans . In this review, a summary of the advances in SAGE technology and its unique attributes and potential applications to the cardiovascular system will be presented.
Pharmacokinetic evaluation of gemcitabine and 2′,2′-difluorodeoxycytidine-5′-triphosphate after prolonged infusion in patients affected by different solid tumors
Authors: L. Cattel, M. Airoldi, L. Delprino, R. Passera, P. Milla, F. Pedani
Journal: Annals of Oncology (2006)
Health-Related Quality of Life During the 10 Years After Diagnosis of Colorectal Cancer: A Population-Based Study
Authors: Lina Jansen, Antje Herrmann, Christa Stegmaier, Susanne Singer, Hermann Brenner, Volker Arndt
Journal: Journal of Clinical Oncology (2011)

Purpose To compare long-term quality of life (QoL) of colorectal cancer survivors with QoL in the general population and investigate changes in QoL of survivors during the 10 years after diagnosis. Patients and Methods Health-related QoL was assessed 1, 3, 5, and 10 years after diagnosis in a population-based cohort starting with 439 patients with colorectal cancer from Saarland, Germany, using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30. QoL after 5 and 10 years and time course of QoL during the 10 years after diagnosis were compared with controls from the general population of Germany, after controlling for sex and age. Results Overall, 234 and 196 patients were still alive after 5 and 10 years, respectively. Of these survivors, 178 (76%) responded in the 5-year follow-up, 133 (68%) in the 10-year follow-up, and 117 (60%) participated in all follow-ups. Over the entire follow-up, younger survivors (age at diagnosis, &lt; 60 years) reported restrictions in role, social, emotional, and cognitive functioning and specific problems like constipation, diarrhea, fatigue, and insomnia. Older survivors (age at diagnosis, ≥ 70 years) reported comparable or even better QoL than controls within the first 3 to 5 years after diagnosis and comparable to worse QoL 5 to 10 years after diagnosis. Conclusion Although younger survivors continuously reported detriments in various QoL dimensions during the 10-year period after diagnosis, detriments in older survivors became apparent in the long run only.
Rapid Isolation of Glomeruli Coupled with Gene Expression Profiling Identifies Downstream Targets in Pod1 Knockout Mice
Authors: Shiying Cui, Chengjin Li, Masatsugu Ema, Jordan Weinstein, Susan E. Quaggin
Journal: Journal of the American Society of Nephrology (2005)

Mouse mutations have provided tremendous insights into the molecular basis of renal and glomerular development. However, genes often play important roles during multiple stages of nephrogenesis, making it difficult to determine the role of a gene in a specific cell lineage such as the podocyte. Conditional gene targeting and chimeric analysis are two possible approaches to dissect the function of genes in specific cell populations. However, these are labor-intensive and costly and require the generation, validation, and analysis of additional transgenic lines. For overcoming these shortcomings and, specifically, for studying the role of gene function in developing glomeruli, a technique to isolate and purify glomeruli from murine embryos was developed. Combined with gene expression profiling, this method was used to identify differentially expressed genes in glomeruli from Pod1 knockout (KO) mice that die in the perinatal period with multiple renal defects. Glomeruli from early developing stages (late S-shape/early capillary loop) onward can be isolated successfully from wild-type and KO kidneys at 18.5 d postcoitus, and RNA can readily be obtained and used for genome-wide microarray analysis. With this approach, 3986 genes that are differently expressed between glomeruli from Pod1 KO and wild-type mice were identified, including a four-fold reduction of α 8 integrin mRNA in glomeruli from Pod1 KO mice that was confirmed by immunostaining. This procedure may be adapted to any transgenic strain, providing a rapid and efficient method to dissect the function of specific genes in glomerular development.
Classification of unknown primary tumors with a data-driven method based on a large microarray reference database
Authors: Kalle A Ojala, Sami K Kilpinen, Olli P Kallioniemi
Journal: Genome Medicine (2011)

We present a new method to analyze cancer of unknown primary origin (CUP) samples. Our method achieves good results with classification accuracy (88% leave-one-out cross validation for primary tumors from 56 categories, 78% for CUP samples), and can also be used to study CUP samples on a gene-by-gene basis. It is not tied to any a priori defined gene set as many previous methods, and is adaptable to emerging new information.
Diagnosis, management and prevention of drug-induced liver injury
Authors: S Verma, N Kaplowitz
Journal: Gut (2009)

Drug-induced liver injury (DILI) is increasingly being recognised as a significant cause of both acute and chronic liver disease. The most commonly implicated agents are paracetamol, antimicrobials, non-steroidal anti-inflammatory drugs, statins, isoniazid and herbal remedies. Drug-induced hepatotoxicity is generally idiosyncratic in nature. The pathogenesis of DILI remains enigmatic, but involves exposure to the toxic agent, mitochondrial injury, failure of adaptation, and innate and adaptive immune responses. Diagnosis of drug-induced liver diseases can be difficult, but the key to causality is to diligently exclude other causes of liver injury, and to identify a characteristic clinical drug-related signature. Management of drug-induced liver injury is symptomatic, with early referral to a liver transplant unit at the first hint of liver failure, especially in those with non-paracetamol-induced liver injury. Prevention of drug hepatotoxicity includes increased vigilance during pre-clinical drug development and clinical trials, alanine aminotransferase monitoring with certain drugs, better marketing strategies, and the future identification of both diagnostic and prognostic biomarkers.
Reduction of Infarct Size and Prevention of Cardiac Rupture in Transgenic Mice Overexpressing FrzA
Authors: Laurent Barandon, Thierry Couffinhal, Jérome Ezan, Pascale Dufourcq, Pierre Costet, Philippe Alzieu, Lionel Leroux, Catherine Moreau, Danièle Dare, Cécile Duplàa
Journal: Circulation (2003)

Background— FrzA/sFRP-1, a secreted, frizzled-related protein and antagonist for the wnt/frizzled pathway, is expressed in the heart and vessels during mouse embryogenesis and adulthood. FrzA is involved in cell cycle control of vascular cells and angiogenesis. We assessed the hypothesis that FrzA could control the healing process after myocardial infarction (MI). Methods and Results— We demonstrated an upregulation of sFRP-1 and distinct wnt and fz member expression after MI. We established transgenic (Tg) mice that overexpress FrzA under a cytomegalovirus promoter and developed a model of MI by coronary artery ligation. FrzA reduced cardiac rupture after MI in Tg (6.5% versus 26.4% in controls; n=165, P &lt;0.01). MI was smaller in Tg at each time point (18±10.8% of left ventricular circumference versus 30±14.2% in controls at day 30; P &lt;0.001). Similar results were found in cryolesion-induced MI. Cardiac function was improved in Tg mice (3800±370 mm Hg/s dP/dt max versus 2800±840 in controls; −2800±440 dP/dt min versus −1800±211 in controls at day 15; P &lt;0.001). Early leukocyte infiltration had decreased in Tg mice during the first week. Apoptotic index was decreased by 50% in Tg mice at day 7. Matrix metalloproteinase-2 and −9 activity was reduced in Tg mice at day 4, and collagen deposition in the scar was increased in Tg mice. Capillary density in the scar was higher in Tg mice (290±103 vessels/mm 2 versus 104±43 in controls at day 15; P &lt;0.001). Vessels were more muscularized, and mean lumen area was 3-fold higher in Tg animals. Conclusions— Overexpression of FrzA, through direct or indirect interaction with different phases of infarct healing, reduced infarct size and improved cardiac function.
Evaluation of macrolides for possible use against multidrug-resistant <i>Mycobacterium tuberculosis</i>
Authors: Anne-Fleur van der Paardt, Bob Wilffert, Onno W. Akkerman, Wiel C.M. de Lange, Dick van Soolingen, Bhanu Sinha, Tjip S. van der Werf, Jos G.W. Kosterink, Jan-Willem C. Alffenaar
Journal: European Respiratory Journal (2015)

Multidrug-resistant tuberculosis (MDR-TB) is a major global health problem. The loss of susceptibility to an increasing number of drugs behoves us to consider the evaluation of non-traditional anti-tuberculosis drugs. Clarithromycin, a macrolide antibiotic, is defined as a group 5 anti-tuberculosis drug by the World Health Organization; however, its role or efficacy in the treatment of MDR-TB is unclear. A systematic review of the literature was conducted to summarise the evidence for the activity of macrolides against MDR-TB, by evaluating in vitro, in vivo and clinical studies. PubMed and Embase were searched for English language articles up to May 2014. Even though high minimum inhibitory concentration values are usually found, suggesting low activity against Mycobacterium tuberculosis , the potential benefits of macrolides are their accumulation in the relevant compartments and cells in the lungs, their immunomodulatory effects and their synergistic activity with other anti-TB drugs. A future perspective may be use of more potent macrolide analogues to enhance the activity of the treatment regimen.
Myocardial Ischemic Injury After Heart Transplantation Is Associated With Upregulation of Vitronectin Receptor (α <sub>v</sub> β <sub>3</sub> ), Activation of the Matrix Metalloproteinase Induction System, and Subsequent Development of Coronary Vasculopathy
Authors: Mohamad H. Yamani, E. Murat Tuzcu, Randall C. Starling, Norman B. Ratliff, Yang Yu, D. Geoffrey Vince, Kimerly Powell, Daniel Cook, Patrick McCarthy, James B. Young
Journal: Circulation (2002)

Myocardial ischemic injury after heart transplantation is associated with subsequent development of graft vasculopathy. Both vitronectin receptor (integrin alpha(v)beta3) and tissue factor play key roles in vascular endothelial cell injury. Matrix metalloproteinases (MMPs) are activated in ischemic injury models.Thirteen patients developed myocardial ischemic injury within 2 weeks of cardiac transplantation (ischemia group). These were compared with 10 transplantation patients who had no evidence of ischemia (control group). Endomyocardial biopsies were evaluated within 2 weeks of transplantation for alpha(v)beta3, tissue factor, and extracellular MMP inducer (EMMPRIN). At 1 year, MMPs were evaluated, and interstitial myocardial fibrosis was quantified. All patients underwent intravascular ultrasound at 1 month and 1 year after transplantation. Compared with control, the ischemia group demonstrated evidence of significant increased expression of alpha(v)beta3 (3.2-fold, P<0.001), tissue factor (2.5-fold, P<0.001), and EMMPRIN (1.9-fold, P=0.01). At 1 year, the ischemia group had a significant increase in myocardial fibrosis (24+/-1.8% versus 14+/-1.1%, P<0.001) and zymographic activity of MMP-2 (1.4-fold, P<0.001), MMP-3 (1.2-fold, P<0.001), and MMP-9 (1.3-fold, P=0.01). Coronary vasculopathy progression was also more advanced in the ischemia group (change in coronary maximal intimal thickness over 1 year 0.54+/-0.1 versus 0.26+/-0.06 mm; P=0.031).Myocardial ischemic injury after cardiac transplantation is associated with upregulation of alpha(v)beta3, tissue factor, and activation of the MMP induction system, which may contribute to the subsequent development of allograft remodeling and vasculopathy.
Maximal Ca2+-activated force elicited by tetanization of ferret papillary muscle and whole heart: mechanism and characteristics of steady contractile activation in intact myocardium.
Authors: E Marban, H Kusuoka, D T Yue, M L Weisfeldt, W G Wier
Journal: Circulation Research (1986)

Rapid (8-12 Hz) stimulation of intact heart muscle treated with ryanodine results in steady contractile activation known as tetanus, the amplitude of which can be graded by changing extracellular Ca2+ concentration ([Ca2+]o). The mechanism of the sustained force generation was explored in ferret papillary muscles by measuring membrane potential and by determining the responsiveness of force and intracellular free Ca2+ concentration ([Ca2+]i, estimated with aequorin) to dihydropyridine Ca channel ligands. Membrane potential during tetani ranged from -25 to -60 mV, suggesting that fast or slow Ca channels, or Na-Ca exchange, might be mediating Ca2+ entry. Dihydropyridine effects indicated that slow Ca channels play a predominant role: The agonist Bay K 8644 (0.3-1 microM) increased force and aequorin luminescence, whereas the antagonist nitrendipine (1-30 microM) abolished the tetanus. Under conditions analogous to those in the papillary muscle experiments, tetani were produced in whole Langendorff-perfused ferret hearts following exposure to ryanodine. Contraction saturated as a function of [Ca2+]o in both papillary muscles and whole hearts; i.e., as [Ca2+]o was increased above 10 mM, no further increase in force or pressure generation occurred. In contrast, aequorin luminescence measured in the papillary muscles showed no such saturation. Thus, maximal Ca2+-activated force (or pressure) was achieved during tetani at [Ca2+]o greater than or equal to 10 mM. Calculations of wall stress during tetani in whole heart (15 mM [Ca2+]o) agree well with direct measurements of maximal tension in papillary muscles (5.84 g/mm2 vs. 6.41 g/mm2, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Hypoadiponectinemia Is Closely Associated With Nonalcoholic Hepatic Steatosis in Obese Subjects
Authors: Giovanni Targher, Lorenzo Bertolini, Luciano Zenari
Journal: Diabetes Care (2004)

Nonalcoholic fatty liver disease is a clinicopathological syndrome that is closely associated with obesity and other metabolic syndrome features (1).

Recent research has shown that adiponectin is a novel adipocyte-derived hormone with antidiabetic and antiatherogenic properties (2). In humans, plasma adiponectin levels are significantly lower in insulin-resistant states (2), thus suggesting that this adipocytokine is an important marker of the metabolic syndrome. Administration of adiponectin to mice has been shown to produce beneficial effects on glucose metabolism (2). Furthermore, administration of this protein was also effective in ameliorating liver biopsy features and liver test results in ob/ob mice (3). Accordingly, after controlling for age, sex, and …
Prospective Determination of Prevalence of Lynch Syndrome in Young Women With Endometrial Cancer
Authors: Karen H. Lu, John O. Schorge, Kerry J. Rodabaugh, Molly S. Daniels, Charlotte C. Sun, Pamela T. Soliman, Kristin G. White, Rajyalakshmi Luthra, David M. Gershenson, Russell R. Broaddus
Journal: Journal of Clinical Oncology (2007)

Age younger than 50 years at the time of colon cancer diagnosis is often used as a screening criterion for Lynch syndrome (hereditary nonpolyposis colorectal cancer syndrome). The purpose of this study was to determine the prevalence of MLH1, MSH2, and MSH6 mutations in an unselected cohort of women diagnosed with endometrial cancer at age younger than 50 years.A prospective, multicenter study was performed at three institutions. After written consent was obtained, germline mutation testing by full sequencing and large deletion analysis of the MLH1, MSH2, and MSH6 genes was performed. Tumor studies included immunohistochemistry of MLH1, MSH2, and MSH6; microsatellite instability analysis; and hypermethylation of the MLH1 promoter.Of the 100 women, nine (9%; 95% CI, 4.2 to 16.4) carried a deleterious germline mutation: seven women with mutations in MSH2, one woman with a mutation in MLH1, and one woman with a mutation in MSH6. Two additional women had molecular studies consistent with the diagnosis of Lynch syndrome. The mean body mass index (BMI) for the entire cohort was 34.4, which is significantly higher than 29.2, the mean BMI for the mutation carriers. Predictors of finding a germline mutation included having a first-degree relative with a Lynch syndrome-associated cancer, endometrial tumor with loss of MSH2 expression, tumors with high microsatellite instability, and lower BMI.In this prospective study of endometrial cancer patients younger than age 50 years, 9% were found to carry germline Lynch syndrome-associated mutations. In addition to young age of onset, family history, BMI, and molecular tumor studies can improve the likelihood of identifying a Lynch syndrome-associated germline mutation in MLH1, MSH2, and MSH6.
Mast cell mediators other than histamine induce pruritus in atopic dermatitis patients: a dermal microdialysis study
Authors: R. Rukwied, G. Lischetzki, F. Mcglone, G. Heyer, M. Schmelz
Journal: British Journal of Dermatology (2000)

While histamine is the crucial mediator of pruritus in type 1 allergic reactions, its role in atopic dermatitis (AD) is unclear. In this study, the role of mast cell mediators in protein extravasation and pruritus was evaluated using intradermal microdialysis. The microdialysis capillaries were used to apply the mast cell degranulating substance compound 48/80 (C48/80; 0.05%) or histamine (0.01%) and also to deliver H1-blockers (cetirizine, 200 microg mL-1) in nine AD patients and nine controls. Large pore size membranes (3000 kDa) enabled simultaneous analysis of protein extravasation. Itch sensation was measured psychophysically and weal and flare reaction were evaluated planimetrically. Protein extravasation induced by histamine and C48/80 was significantly reduced in AD patients. Blockade of H1-receptors by cetirizine significantly reduced C48/80-induced protein extravasation in AD patients and controls to an identical level. C48/80-induced pruritus was abolished by cetirizine in controls, whereas pruritus in AD patients was unchanged after H1 blockade. We conclude that mast cell mediators others than histamine are involved in C48/80-induced pruritus in AD patients. Whether the reduced capacity of AD patients to induce protein extravasation is of pathophysiological relevance for pruritus remains to be established.
α-Catulin Drives Metastasis by Activating ILK and Driving an αvβ3 Integrin Signaling Axis
Authors: Chen-Hsien Liang, Szu-Ying Chiu, I-Ling Hsu, Yi-Ying Wu, Yao-Tsung Tsai, Jhen-Yu Ke, Szu-Hua Pan, Yi-Chiung Hsu, Ker-Chau Li, Pan-Chyr Yang, Yuh-Ling Chen, Tse-Ming Hong
Journal: Cancer Research (2012)

α-Catulin is an oncoprotein that helps sustain proliferation by preventing cellular senescence. Here, we report that α-catulin also drives malignant invasion and metastasis. α-Catulin was upregulated in highly invasive non-small cell lung cancer (NSCLC) cell lines, where its ectopic expression or short-hairpin RNA-mediated attenuation enhanced or limited invasion or metastasis, respectively. α-Catulin interacted with integrin-linked kinase (ILK), a serine/threonine protein kinase implicated in cancer cell proliferation, antiapoptosis, invasion, and angiogenesis. Attenuation of ILK or α-catulin reciprocally blocked cell migration and invasion induced by the other protein. Mechanistic investigations revealed that α-catulin activated Akt-NF-κB signaling downstream of ILK, which in turn led to increased expression of fibronectin and integrin αvβ3. Pharmacologic or antibody-mediated blockade of NF-κB or αvβ3 was sufficient to inhibit α-catulin-induced cell migration and invasion. Clinically, high levels of expression of α-catulin and ILK were associated with poor overall survival in patients with NSCLC. Taken together, our study shows that α-catulin plays a critical role in cancer metastasis by activating the ILK-mediated Akt-NF-κB-αvβ3 signaling axis.