tbuckley/cabot-search huggingface dataset:
<i>MYC</i> Can Induce DNA Breaks <i>In vivo</i> and <i>In vitro</i> Independent of Reactive Oxygen Species
Authors: Suma Ray, Kondala R. Atkuri, Debabrita Deb-Basu, Adam S. Adler, Howard Y. Chang, Leonore A. Herzenberg, Dean W. Felsher
Journal: Cancer Research (2006)

Abstract MYC overexpression is thought to initiate tumorigenesis by inducing cellular proliferation and growth and to be restrained from causing tumorigenesis by inducing cell cycle arrest, cellular senescence, and/or apoptosis. Here we show that MYC can induce DNA breaks both in vitro and in vivo independent of increased production of reactive oxygen species (ROS). We provide an insight into the specific circumstances under which MYC generates ROS in vitro and propose a possible mechanism. We found that MYC induces DNA double-strand breaks (DSBs) independent of ROS production in murine lymphocytes in vivo as well as in normal human foreskin fibroblasts (NHFs) in vitro in normal (10%) serum, as measured by γH2AX staining. However, NHFs cultured in vitro in low serum (0.05%) and/or ambient oxygen saturation resulted in ROS-associated oxidative damage and DNA single-strand breaks (SSBs), as measured by Ape-1 staining. In NHFs cultured in low versus normal serum, MYC induced increased expression of CYP2C9, a gene product well known to be associated with ROS production. Specific inhibition of CYP2C9 by small interfering RNA was shown to partially inhibit MYC-induced ROS production. Hence, MYC overexpression can induce ROS and SSBs under some conditions, but generally induces widespread DSBs in vivo and in vitro independent of ROS production. (Cancer Res 2006; 66(13): 6598-605)
Physical Activity, High-Sensitivity C-Reactive Protein, and Total and Cardiovascular Disease Mortality in Type 2 Diabetes
Authors: Teemu Vepsäläinen, Minna Soinio, Jukka Marniemi, Seppo Lehto, Auni Juutilainen, Markku Laakso, Tapani Rönnemaa
Journal: Diabetes Care (2011)

OBJECTIVE Physical activity reduces high-sensitivity C-reactive protein (hs-CRP), cardiovascular disease (CVD), and total mortality in type 2 diabetic patients. However, it is not known whether the effects of physical activity on mortality depend on the levels of hs-CRP in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS We prospectively followed-up on 569 type 2 diabetic patients, aged 45–64 years, who were free of CVD at baseline. Participants were stratified according to the level of hs-CRP (&amp;lt;1.0, 1.0–3.0, or &amp;gt;3.0 mg/L) and the degree of physical activity (0–4 metabolic equivalent tasks [METs] or &amp;gt;4 METs). The Cox proportional hazards model was used to estimate the joint association between physical activity and hs-CRP levels and the risk of mortality. RESULTS During an 18-year follow-up, 356 patients died, 217 of whom died of CVD. Those who were physically more active had significantly reduced total, CVD and coronary heart disease (CHD) mortality among patients with elevated hs-CRP levels (&amp;gt;3 mg/L). These findings persisted in multivariable analyses. However, in patients with an hs-CRP level &amp;lt;1 mg/L or between 1 and 3 mg/L, there was no statistically significant relationship between physical activity and CVD or CHD mortality. CONCLUSIONS Physical activity reduces total, CVD, and CHD mortality in type 2 diabetic patients with elevated hs-CRP levels. This suggests that the anti-inflammatory effect of physical activity may counteract increased CVD and CHD morbidity and mortality associated with high CRP levels.
An autocrine or a paracrine role of adrenomedullin in modulating cardiac fibroblast growth
Authors: T Tsuruda
Journal: Cardiovascular Research (1999)

Objective: The aim of the present study was to determine the role of adrenomedullin (AM) in cardiac fibroblasts. Methods: The production and secretion of AM were examined in cultured neonatal rat cardiac fibroblasts, and the effects of AM on proliferation and protein synthesis of these cells were assessed by [3H]thymidine and [3H]phenylalanine incorporation, respectively. Results: Cultured cardiac fibroblasts secreted AM into the medium time-dependently at a rate of 20.3±3.0 fmol/5×104 cells/48 h, mean±S.D. Northern blot analysis showed expression of preproAM mRNA of 1.6 kb in these cells. In addition, 10−6 mol/l of angiotensin II (Ang II) and endothelin-1 (ET-1) significantly increased the AM secretion by 55 and 48%, respectively. Synthetic AM significantly reduced 10−6 mol/l Ang II- or 10−7 mol/l ET-1-stimulated [3H]thymidine and [3H]phenylalanine incorporation in a dose-dependent manner, and these effects were attenuated by a calcitonin gene-related peptide (CGRP) type 1 receptor antagonist, CGRP(8-37). Synthetic AM also had a dose-dependent stimulatory effect on cAMP accumulation in these cells, which was significantly attenuated by CGRP(8-37). A cAMP analogue, 8-bromo-cAMP, mimicked the AM effects, inhibiting the Ang II-stimulated [3H]thymidine and [3H]phenylalanine incorporation. Blockage of the effect of endogenous AM by anti-AM monoclonal antibody not only significantly reduced the basal level of intracellular cAMP, but also enhanced the [3H]thymidine and [3H]phenylalanine incorporation into the cells. Conclusions: Cultured neonatal rat cardiac fibroblasts produce and secrete AM, and the secreted AM may inhibit proliferation and protein synthesis of these cells. AM may exert these inhibitory effects partly by elevating intracellular cAMP. It is suggested that AM has an important role in modulating the growth of cardiac fibroblasts in an autocrine or a paracrine manner.
Novel targeted therapies for eosinophilic disorders
Authors: Michael E. Wechsler, Patricia C. Fulkerson, Bruce S. Bochner, Gail M. Gauvreau, Gerald J. Gleich, Tim Henkel, Roland Kolbeck, Sameer K. Mathur, Hector Ortega, Jatin Patel, Calman Prussin, Paolo Renzi, Marc E. Rothenberg, Florence Roufosse, Dagmar Simon, Hans-Uwe Simon, Andrew Wardlaw, Peter F. Weller, Amy D. Klion
Journal: Journal of Allergy and Clinical Immunology (2012)
Airway Epithelial Transcription Factor NK2 Homeobox 1 Inhibits Mucous Cell Metaplasia and Th2 Inflammation
Authors: Yutaka Maeda, Gang Chen, Yan Xu, Hans Michael Haitchi, Lingling Du, Angela R. Keiser, Peter H. Howarth, Donna E. Davies, Stephen T. Holgate, Jeffrey A. Whitsett
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Airway mucous cell metaplasia and chronic inflammation are pathophysiological features that influence morbidity and mortality associated with asthma and other chronic pulmonary disorders. Elucidation of the molecular mechanisms regulating mucous metaplasia and hypersecretion provides the scientific basis for diagnostic and therapeutic opportunities to improve the care of chronic pulmonary diseases.To determine the role of the airway epithelial–specific transcription factor NK2 homeobox 1 (NKX2-1, also known as thyroid transcription factor-1 [TTF-1]) in mucous cell metaplasia and lung inflammation.Expression of NKX2-1 in airway epithelial cells from patients with asthma was analyzed. NKX2-1 +/-gene targeted or transgenic mice expressing NKX2-1 in conducting airway epithelial cells were sensitized to the aeroallergen ovalbumin. In vitro studies were used to identify mechanisms by which NKX2-1 regulates mucous cell metaplasia and inflammation.NKX2-1 was suppressed in airway epithelial cells from patients with asthma. Reduced expression of NKX2-1 in heterozygous NKX2-1 +/- gene targeted mice increased mucous metaplasia in the small airways after pulmonary sensitization to ovalbumin. Conversely, mucous cell metaplasia induced by aeroallergen was inhibited by expression of NKX2-1 in the respiratory epithelium in vivo. Genome-wide mRNA analysis of lung tissue from ovalbumin-treated mice demonstrated that NKX2-1 inhibited mRNAs associated with mucous metaplasia and Th2-regulated inflammation,including Spdef, Ccl17, and Il13. In vitro, NKX2-1 inhibited SPDEF, a critical regulator of airway mucous cell metaplasia,and the Th2 chemokine CCL26.The present data demonstrate a novel function for NKX2-1 in a gene network regulating mucous cell metaplasia and allergic inflammation in the respiratory epithelium.
Oxidative Stress, Obesity, and Breast Cancer Risk: Results From the Shanghai Women's Health Study
Authors: Qi Dai, Yu-Tang Gao, Xiao-Ou Shu, Gong Yang, Ginger Milne, Qiuyin Cai, Wanqing Wen, Nathaniel Rothman, Hui Cai, Honglan Li, Yongbing Xiang, Wong-Ho Chow, Wei Zheng
Journal: Journal of Clinical Oncology (2009)

Increased reactive oxygen species may exhaust the antioxidant capability of human defense systems, leading to oxidative stress and cancer development. Urinary F2-isoprostanes, secondary end products of lipid peroxidation, are more accurate markers of oxidative stress than other available biomarkers. No prospective study has investigated whether levels of 15-F(2t)-isoprostane (15-F(2t)-IsoP) and its metabolite 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP (15-F(2t)-IsoPM) are related to breast cancer risk.We conducted a nested case-control study within the Shanghai Women's Health Study, a population-based cohort study of 74,942 Chinese women between 40 and 70 years of age. Prediagnostic urinary 15-F(2t)-IsoP and 15-F(2t)-IsoPM were measured by gas chromatography mass spectrometry for 436 breast cancer cases and 852 individually matched controls.Urinary excretion of isoprostanes was not significantly different between cases and controls. However, among overweight women, levels of isoprostanes were positively associated with breast cancer risk, which became stronger with increasing body mass index (BMI). Among women with a BMI > or = 29, the odds ratio (OR) increased to 10.27 (95% CI, 2.41 to 43.80) for the highest compared with the lowest tertile of 15-F(2t)-IsoPM (P for trend = .003; P for interaction = .0004). In contrast, 15-F(2t)-IsoP and 15-F(2t)-IsoPM were inversely associated with breast cancer risk among nonoverweight women. Among women with a BMI < or = 23, breast cancer risk was reduced with increasing 15-F(2t)-IsoP levels in a dose-response manner (P for trend = .006), with an OR of 0.46 (95% CI, 0.26 to 0.80) for the highest tertile versus the lowest (P for interaction = .006).Our results suggest that the role of oxidative stress in breast cancer development may depend on adiposity.
<i>Helicobacter pylori</i> Eradication Prevents Progression of Gastric Cancer in Hypergastrinemic INS-GAS Mice
Authors: Chung-Wei Lee, Barry Rickman, Arlin B. Rogers, Zhongming Ge, Timothy C. Wang, James G. Fox
Journal: Cancer Research (2008)

Helicobacter pylori infection results in chronic gastritis, which may progress to gastric cancer. In this study, we investigated the efficacy of H. pylori eradication in preventing the progression of gastritis to gastric cancer in H. pylori-infected transgenic INS-GAS mice. H. pylori infection induced severe dysplasia and gastric cancer classified as high-grade and low-grade gastrointestinal intraepithelial neoplasia (GIN) in INS-GAS mice at 28 weeks postinfection (WPI). H. pylori eradication therapy using omeprazole, metronidazole, and clarithromycin was administered p.o. at 8, 12, or 22 WPI. Compared with untreated infected mice, H. pylori eradication at 8, 12, and 22 WPI significantly reduced the severity of dysplasia (P < 0.01). Moreover, H. pylori eradication at 8 WPI completely prevented the development of GIN (P < 0.001). Although not as effective as early antimicrobial treatment, prevention of progression to high-grade GIN was achieved by H. pylori eradication at 12 and 22 WPI (P < 0.05). Consistent with reduced gastric pathology, H. pylori eradication at all time points significantly down-regulated gastric Interferon-gamma, tumor necrosis factor-alpha, inducible nitric oxide synthase, and Reg 1 mRNA levels (P < 0.05) and reduced epithelial proliferation in the corpus (P < 0.01) compared with untreated infected mice. We concluded that H. pylori eradication prevented gastric cancer to the greatest extent when antibiotics are given at an early point of infection, but that eradication therapy given at a later time point delayed the development of severe dysplastic lesions.
Retroviral Insertional Mutagenesis Identifies Genes that Collaborate with <i>NUP98-HOXD13</i> during Leukemic Transformation
Authors: Christopher Slape, Helge Hartung, Ying-Wei Lin, Juraj Bies, Linda Wolff, Peter D. Aplan
Journal: Cancer Research (2007)

Abstract The t(2;11)(q31;p15) chromosomal translocation results in a fusion between the NUP98 and HOXD13 genes and has been observed in patients with myelodysplastic syndrome (MDS) or acute myelogenous leukemia. We previously showed that expression of the NUP98-HOXD13 (NHD13) fusion gene in transgenic mice results in an invariably fatal MDS; approximately one third of mice die due to complications of severe pancytopenia, and about two thirds progress to a fatal acute leukemia. In the present study, we used retroviral insertional mutagenesis to identify genes that might collaborate with NHD13 as the MDS transformed to an acute leukemia. Newborn NHD13 transgenic mice and littermate controls were infected with the MOL4070LTR retrovirus. The onset of leukemia was accelerated, suggesting a synergistic effect between the NHD13 transgene and the genes neighboring retroviral insertion events. We identified numerous common insertion sites located near protein-coding genes and confirmed dysregulation of a subset of these by expression analyses. Among these genes were Meis1, a known collaborator of HOX and NUP98-HOX fusion genes, and Mn1, a transcriptional coactivator involved in human leukemia through fusion with the TEL gene. Other putative collaborators included Gata2, Erg, and Epor. Of note, we identified a common insertion site that was &amp;gt;100 kb from the nearest coding gene, but within 20 kb of the miR29a/miR29b1 microRNA locus. Both of these miRNA were up-regulated, demonstrating that retroviral insertional mutagenesis can target miRNA loci as well as protein-coding loci. Our data provide new insights into NHD13-mediated leukemogenesis as well as retroviral insertional mutagenesis mechanisms. [Cancer Res 2007;67(11):5148–55]
Posttherapy [<sup>18</sup>F] Fluorodeoxyglucose Positron Emission Tomography in Carcinoma of the Cervix: Response and Outcome
Authors: Perry W. Grigsby, Barry A. Siegel, Farrokh Dehdashti, Janet Rader, Imran Zoberi
Journal: Journal of Clinical Oncology (2004)

The aim of this study was to evaluate response to therapy using posttherapy molecular imaging with [(18)F] fluorodeoxyglucose (FDG), and to compare the response with patient outcome.This was a retrospective medical record review of 152 patients with carcinoma of the cervix. All patients underwent a pre- and posttreatment whole-body positron emission tomography (PET) imaging scan with FDG. Patients were treated with external irradiation and intracavitary brachytherapy, and most received concurrent weekly cisplatin. Posttherapy whole-body FDG-PET was performed 1 to 12 months (mean, 3 months) after completion of treatment.The posttherapy PET did not show any abnormal FDG uptake in 114 patients, and their 5-year cause-specific survival estimate was 80%. There was persistent (in the irradiated region) abnormal FDG uptake in the cervix or lymph nodes in 20 patients. Their 5-year cause-specific survival estimate was 32%. New anatomic sites (in unirradiated regions) of abnormal FDG uptake were present in 18 patients, and none were alive at 5 years. A Cox proportional hazards model of survival outcome indicated that any abnormal posttherapy FDG uptake (persistent or new) was the most significant prognostic factor for developing metastatic disease and death from cervical cancer when compared with pretreatment- and treatment-related prognostic factors (P <.0001).Posttherapy abnormal FDG uptake (persistent or new) as detected by whole-body PET measures tumor response and might be predictive of tumor recurrence and death from cervical cancer. Prospective validation of these results is warranted.
A comprehensive theory of human mating must explain between-sex and within-sex differences in mating strategies
Authors: April L. Bleske, David M. Buss
Journal: Behavioral and Brain Sciences (2000)

Gangestad &amp; Simpson make a major contribution by highlighting the importance of mate choice for good genes, the costs of alternative strategies, and tradeoffs inherent in human mating. By downplaying sex differences and ignoring the nongenetic adaptive benefits of short term mating, however, they undermine their goal of “strategic pluralism” by presenting a theory devoid of many documented complexities of human mating.
STUDIES ON IMMUNITY IN CANCERS OF THE WHITE RAT
Authors: I. Levin, M. J. Sittenfield
Journal: The Journal of Experimental Medicine (1911)

In a previous communication, one of the present writers ( I ) showed that the result of tumor implantation is determined by two factors : first, whether or not the implanted tumor becomes ingrafted, and second, the rate of its growth if ingrafted.The mechanism of ingrafting is common to tumor and normal tissue.Thus, Ribbert (2) has successfully implanted human skin into the ear of the rabbit.On the other hand, the ultimate fate and character of the graft depends on the rate of growth of the implanted tissue.If the growth of the latter proceeds at approximately the same rate as that of the surrounding tissue, the implanted tissue develops into a small nodule which is ultimately absorbed.On the other hand, if the intensity of the cell proliferation in the implanted tumor exceeds that of the surrounding tissue, there will develop a large malignant tumor.The rate of growth of an implanted tumor and with it the ultimate character of the tumor depend upon an interaction between the power of proliferation of the tumor cell and the resistance of the host.The mere grafting of the tumor is independent of the phenomenon of cancer immunity.A great deal of the confusion and controversy that exists in the attempted analysis of the results of the work on cancer immunity is caused by this lack of appreciation of the coexistence of the two factors determining the outcome of the tumor implantation.It seemed, therefore, desirable to undertake a revision of the work on cancer immunity.
PERSISTENCE OF ANTIBIOTICS IN BLOOD OF PATIENTS WITH ACUTE RENAL FAILURE. II. CHLORAMPHENICOL AND ITS METABOLIC PRODUCTS IN THE BLOOD OF PATIENTS WITH SEVERE RENAL DISEASE OR HEPATIC CIRRHOSIS*†
Authors: Calvin M. Kunin, Anthony J. Glazko, Maxwell Finland
Journal: Journal of Clinical Investigation (1959)

lt is known that the kidney plays a major but variable role in the elimination of most of the antibiotics that are used systemically.Since these drugs are often employed in the prevention and treatment of infections in patients with severe renal disease, it becomes essential, both for the choice of agents and for their most effective use, to know how the different antibiotics are handled by the patient with impaired renal function.The present series of studies was therefore under- taken with a view to providing a basis for the rational choice of antibiotics and their dosage in such patients.The persistence of several other commonly used antibiotics in the blood of pa- tients with anuria and severe renal impairment was described in other papers of this series (2, 3).This paper is concerned with the overall metabo- lism of chloramphenicol in similar patients.In addition, since the liver is also involved in the metabolism of chloramphenicol, studies in a few patients with severe hepatic cirrhosis are also included.The structure of chloramphenicol and possible sites of chemical alterations as they occur in the body are shown in Figure 1.A summary of what is currently known about the metabolism of chloramphenicol in man is presented schematically in Figure 2. Following the adminstration of chlor-
Bone Marrow Stem Cells Contribute to Healing of the Kidney
Authors: Richard Poulsom, Malcolm R. Alison, Terry Cook, Rosemary Jeffery, Eoin Ryan, Stuart J. Forbes, Toby Hunt, Susannah Wyles, Nicholas A. Wright
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. A variety of recent studies support the existence of pathways, in adult humans and rodents, that allow adult stem cells to be surprisingly flexible in their differentiation repertoires. Termed plasticity, this property allows adult stem cells, assumed until now to be committed to generating a fixed range of progeny, on relocation to switch to make other specialized sets of cells appropriate to their new niche. Cells normally present within the bone marrow seem particularly flexible and are able to contribute usefully to many recipient organs. In studies of the liver, bone marrow–derived cells are seen with specialized structural and metabolic adaptations commensurate with their new locations, and these may be abundant, even sufficient, to rescue recipient mice from genetic defects and with evidence that they have proliferated <i>in situ</i>. In the kidney, several studies provide evidence for the presence of "reprogrammed" cells, but in most, it remains possible that cells arrive and redifferentiate but are no longer stem cells. Nevertheless, that appropriately differentiated cells are delivered deep within organs simply by injection of bone marrow cells should make us think differently about the way organs regenerate and repair. Migratory pathways for multipotential cells could be exploited to effect repairs using an individual's own stem cells, perhaps after gene therapy. This concept makes it clear that a transplanted organ would in time become affected by the genetic susceptibilities of the recipient, because of phenotypes that are expressed when trafficking cells incorporate and differentiate. E-mail: richard.poulsom@cancer.org.uk
CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency
Authors: Menno C. van Zelm, Julie Smet, Brigitte Adams, Françoise Mascart, Liliane Schandené, Françoise Janssen, Alina Ferster, Chiung-Chi Kuo, Shoshana Levy, Jacques J.M. van Dongen, Mirjam van der Burg
Journal: Journal of Clinical Investigation (2010)

Antibody deficiencies constitute the largest group of symptomatic primary immunodeficiency diseases. In several patients, mutations in CD19 have been found to underlie disease, demonstrating the critical role for the protein encoded by this gene in antibody responses; CD19 functions in a complex with CD21, CD81, and CD225 to signal with the B cell receptor upon antigen recognition. We report here a patient with severe nephropathy and profound hypogammaglobulinemia. The immunodeficiency was characterized by decreased memory B cell numbers, impaired specific antibody responses, and an absence of CD19 expression on B cells. The patient had normal CD19 alleles but carried a homozygous CD81 mutation resulting in a complete lack of CD81 expression on blood leukocytes. Retroviral transduction and glycosylation experiments on EBV-transformed B cells from the patient revealed that CD19 membrane expression critically depended on CD81. Similar to CD19-deficient patients, CD81-deficient patients had B cells that showed impaired activation upon stimulation via the B cell antigen receptor but no overt T cell subset or function defects. In this study, we present what we believe to be the first antibody deficiency syndrome caused by a mutation in the CD81 gene and consequent disruption of the CD19 complex on B cells. These findings may contribute to unraveling the genetic basis of antibody deficiency syndromes and the nonredundant functions of CD81 in humans.