tbuckley/cabot-search huggingface dataset:
Chimeric Genes as a Source of Rapid Evolution in Drosophila melanogaster
Authors: R. L. Rogers, D. L. Hartl
Journal: Molecular Biology and Evolution (2011)

Chimeric genes form through the combination of portions of existing coding sequences to create a new open reading frame.These new genes can create novel protein structures that are likely to serve as a strong source of novelty upon which selection can act.We have identified 14 chimeric genes that formed through DNA-level mutations in Drosophila melanogaster, and investigate expression profiles, domain structures, and population genetics for each of these genes to examine their potential to effect adaptive evolution.We find that chimeric gene formation commonly produces mid-domain breaks and unites portions of wholly unrelated peptides, creating novel protein structures that are entirely distinct from other constructs in the genome.These new genes are often involved in selective sweeps.We further find a disparity between chimeric genes that have recently formed and swept to fixation vs. chimeric genes that have been preserved over long periods of time, suggesting that preservation and adaptation are distinct processes.Finally, we demonstrate that chimeric gene formation can produce qualitative expression changes that are difficult to mimic through duplicate gene formation, and that extremely young chimeric genes (d S < 0.03 are more likely to be associated with selective sweeps than duplicate genes of the same age.Hence, chimeric genes can serve as an exceptional source of genetic novelty that can have a profound influence on adaptive evolution in D. melanogaster.
Absence or Low Expression of Fas-Associated Protein with Death Domain in Acute Myeloid Leukemia Cells Predicts Resistance to Chemotherapy and Poor Outcome
Authors: Léa Tourneur, Stéphanie Delluc, Vincent Lévy, Françoise Valensi, Isabelle Radford-Weiss, Ollivier Legrand, Jacques Vargaftig, Charlotte Boix, Elizabeth A. Macintyre, Bruno Varet, Gilles Chiocchia, Agnès Buzyn
Journal: Cancer Research (2004)

Abstract In acute myeloid leukemia (AML), coexpression of death receptors and ligands of the tumor necrosis factor (TNF) receptor/TNF-α superfamily on leukemic cells after chemotherapy is not always accompanied by apoptosis, suggesting that the apoptotic death receptor signaling pathway is disrupted. Because Fas-associated protein with death domain (FADD) is the main adaptor for transmitting the Fas, TNF-related apoptosis-inducing ligand receptors, and TNF receptor 1 death signal, expression of FADD was analyzed by Western blot and immunocytochemistry in leukemic cells of 70 de novo AML patients treated with the European Organization of Research and Treatment of Cancer AML-10 randomized trial before initiation of induction chemotherapy. Thirty seven percent of patients (17 of 46) with FADD negative/low (FADD−/low) leukemic cells had a primary refractory disease compared with 12% of FADD+ patients (3 of 24; P = 0.05). FADD−/low expression was significantly associated with a worse event-free survival [EFS (P = 0.04)] and overall survival (P = 0.04). In multivariate analysis, FADD−/low protein expression was independently associated with a poor EFS and overall survival (P = 0.002 and P = 0.026, respectively). Importantly, FADD−/low protein expression predicted poor EFS even in patients with standard- or good-risk AML (P = 0.009). Thus, we identified low or absent expression of the FADD protein in leukemic cells at diagnosis as a poor independent prognostic factor that can predict worse clinical outcome even for patients with standard- or good-risk AML.
A Human Breast Cell Model of Preinvasive to Invasive Transition
Authors: Aylin Rizki, Valerie M. Weaver, Sun-Young Lee, Gabriela I. Rozenberg, Koei Chin, Connie A. Myers, Jamie L. Bascom, Joni D. Mott, Jeremy R. Semeiks, Leslie R. Grate, I. Saira Mian, Alexander D. Borowsky, Roy A. Jensen, Michael O. Idowu, Fanqing Chen, David J. Chen, Ole W. Petersen, Joe W. Gray, Mina J. Bissell
Journal: Cancer Research (2008)

A crucial step in human breast cancer progression is the acquisition of invasiveness. There is a distinct lack of human cell culture models to study the transition from preinvasive to invasive phenotype as it may occur "spontaneously" in vivo. To delineate molecular alterations important for this transition, we isolated human breast epithelial cell lines that showed partial loss of tissue polarity in three-dimensional reconstituted basement membrane cultures. These cells remained noninvasive; however, unlike their nonmalignant counterparts, they exhibited a high propensity to acquire invasiveness through basement membrane in culture. The genomic aberrations and gene expression profiles of the cells in this model showed a high degree of similarity to primary breast tumor profiles. The xenograft tumors formed by the cell lines in three different microenvironments in nude mice displayed metaplastic phenotypes, including squamous and basal characteristics, with invasive cells exhibiting features of higher-grade tumors. To find functionally significant changes in transition from preinvasive to invasive phenotype, we performed attribute profile clustering analysis on the list of genes differentially expressed between preinvasive and invasive cells. We found integral membrane proteins, transcription factors, kinases, transport molecules, and chemokines to be highly represented. In addition, expression of matrix metalloproteinases MMP9, MMP13, MMP15, and MMP17 was up-regulated in the invasive cells. Using small interfering RNA-based approaches, we found these MMPs to be required for the invasive phenotype. This model provides a new tool for dissection of mechanisms by which preinvasive breast cells could acquire invasiveness in a metaplastic context.
Early Detection of Tumor Cells by Innate Immune Cells Leads to Treg Recruitment through CCL22 Production by Tumor Cells
Authors: Julien Faget, Cathy Biota, Thomas Bachelot, Michael Gobert, Isabelle Treilleux, Nadège Goutagny, Isabelle Durand, Sophie Léon-Goddard, Jean Yves Blay, Christophe Caux, Christine Ménétrier-Caux
Journal: Cancer Research (2011)

Abstract In breast carcinomas, patient survival seems to be negatively affected by the recruitment of regulatory T cells (Treg) within lymphoid aggregates by CCL22. However, the mechanisms underpinning this process, which may be of broader significance in solid tumors, have yet to be described. In this study, we determined how CCL22 production is controlled in tumor cells. In human breast carcinoma cell lines, CCL22 was secreted at low basal levels that were strongly increased in response to inflammatory signals [TNF-α, IFN-γ, and interleukin (IL)-1β], contrasting with CCL17. Primary breast tumors and CD45+ infiltrating immune cells appeared to cooperate in driving CCL22 secretion, as shown clearly in cocultures of breast tumor cell lines and peripheral blood mononuclear cells (PBMC) or their supernatants. We determined that monocyte-derived IL-1β and TNF-α are key players as monocyte depletion or neutralization of these cytokines attenuated secretion of CCL22. However, when purified monocytes were used, exogenous human IFN-γ was also required to generate this response suggesting a role for IFN-γ–producing cells within PBMCs. In this setting, we found that human IFN-γ could be replaced by the addition of (i) IL-2 or K562-activated natural killer (NK) cells or (ii) resting NK cells in the presence of anti-MHC class I antibody. Taken together, our results show a dialogue between NK and tumor cells leading to IFN-γ secretion, which in turn associates with monocyte-derived IL-1β and TNF-α to drive production of CCL22 by tumor cells and subsequent recruitment of Treg. As one validation of this conclusion in primary breast tumors, we showed that NK cells and macrophages tend to colocalize within tumors. In summary, our findings suggest that at early times during tumorigenesis, the detection of tumor cells by innate effectors (monocytes and NK cells) imposes a selection for CCL22 secretion that recruits Treg to evade this early antitumor immune response. Cancer Res; 71(19); 6143–52. ©2011 AACR.
Activated expression of the chemokine Mig after chemotherapy contributes to chemotherapy-induced bone marrow suppression and lethal toxicity
Authors: Huili Lu, Shunying Zhu, Lan Qian, Di Xiang, Wu Zhang, Aifang Nie, Jin Gao, Mingyuan Wu, Jinming Gao, Bao Lu, Yan Yu, Wei Han, Anja Moldenhauer
Journal: Blood (2012)
Analysis of endotoxin effects on the intact pulmonary circulation
Authors: B Lambermont
Journal: Cardiovascular Research (1999)

Objective: The mechanism of sustained alterations in pulmonary hemodynamics during endotoxin shock remains unclear. To gain more detailed knowledge we used the four-element windkessel model as a descriptor of the pulmonary circuit. Methods: Consecutive changes in characteristic resistance (R1), vascular compliance (C), input resistance (R2) and inductance (L) were continuously assessed following injection of endotoxin in 6 anaesthetised pigs, and were compared with the corresponding values measured in a similar group of sham-operated animals. Results: Endotoxin challenge resulted in a biphasic pulmonary artery pressure response. Blood flow decreased progressively from 2.8±0.2 l/min to 2±0.2 l/min. Ohmic pulmonary vascular resistance (PVR) increased gradually from 0.2±0.04 to 0.76±0.1 mm Hg s ml−1. The early increase in PAP (from 14±2 to 27±4 mm Hg) was mediated by changes in both R1 (from 0.04±0.01 to 0.06±0.01 mm Hg s ml−1) and R2 (from 0.16±0.04 to 0.61±0.2 mm Hg s ml−1). These responses, in turn, altered the proximal vascular compliance. A subsequent increase in PAP (from 27±2 to 32±3 mm Hg) paralleled the specific decline in distal pulmonary vasculature compliance from 0.84±0.1 to 0.65±0.1 ml/mmHg. Analysis of the time course of PVR did not allow us to distinguish between vasoconstriction and stiffening of the vascular tree as mechanisms accounting for PAP changes. Conclusions: Endotoxemia leads to pulmonary hypertension, which is a result of constriction of proximal pulmonary arteries during the early phase, whereas the late phase is characterised by a decline in distal pulmonary vasculature compliance.
Health Care and Public Service Use and Costs Before and After Provision of Housing for Chronically Homeless Persons With Severe Alcohol Problems
Authors: Mary E. Larimer, Daniel K. Malone, Michelle D. Garner, David C. Atkins, Bonnie Burlingham, Heather S. Lonczak, Kenneth Tanzer, Joshua Ginzler, Seema L. Clifasefi, William G. Hobson, G. Alan Marlatt
Journal: JAMA (2009)

<h3>Context</h3>Chronically homeless individuals with severe alcohol problems often have multiple medical and psychiatric problems and use costly health and criminal justice services at high rates.<h3>Objective</h3>To evaluate association of a “Housing First” intervention for chronically homeless individuals with severe alcohol problems with health care use and costs.<h3>Design, Setting, and Participants</h3>Quasi-experimental design comparing 95 housed participants (with drinking permitted) with 39 wait-list control participants enrolled between November 2005 and March 2007 in Seattle, Washington.<h3>Main Outcome Measures</h3>Use and cost of services (jail bookings, days incarcerated, shelter and sobering center use, hospital-based medical services, publicly funded alcohol and drug detoxification and treatment, emergency medical services, and Medicaid-funded services) for Housing First participants relative to wait-list controls.<h3>Results</h3>Housing First participants had total costs of $8 175 922 in the year prior to the study, or median costs of $4066 per person per month (interquartile range [IQR], $2067-$8264). Median monthly costs decreased to $1492 (IQR, $337-$5709) and $958 (IQR, $98-$3200) after 6 and 12 months in housing, respectively. Poisson generalized estimating equation regressions using propensity score adjustments showed total cost rate reduction of 53% for housed participants relative to wait-list controls (rate ratio, 0.47; 95% confidence interval, 0.25-0.88) over the first 6 months. Total cost offsets for Housing First participants relative to controls averaged $2449 per person per month after accounting for housing program costs.<h3>Conclusions</h3>In this population of chronically homeless individuals with high service use and costs, a Housing First program was associated with a relative decrease in costs after 6 months. These benefits increased to the extent that participants were retained in housing longer.
Chronic hyperglycemia with secondary hyperinsulinemia inhibits the maturational response of fetal lamb lungs to cortisol.
Authors: D Warburton
Journal: Journal of Clinical Investigation (1983)

I tested the hypothesis that chronic hyperglycemia with secondary hyperinsulinemia inhibits the stimulation of fetal lung maturation by cortisol. Glucose was infused (16 +/- 2 mg/kg per min, mean +/- SE) from 112 through 130 d gestation into five chronically catheterised twin fetal lambs from which tracheal fluid could be collected. In addition, cortisol was infused (420 micrograms/h) from 128 through 130 d gestation into both the five glucose-treated twins and the five twin controls. Serum glucose (48 +/- 2 mg/dl) and insulin levels (45 +/- 3 microU/ml) were significantly higher in the glucose-treated fetuses than serum glucose (23 +/- 2 mg/dl, P less than 0.001) and insulin (15 +/- 3 microU/ml, P less than 0.001) in the controls. Serum cortisol levels were less than 2 micrograms/dl before 128 d gestation and rose to greater than 6 micrograms/dl, P less than 0.001 during cortisol infusion in both the glucose-treated and control fetuses. Cortisol treatment of control fetuses was associated with a 4.8-fold increase in surface active material (SAM) flux into tracheal fluid, and a 7.7-fold increase in total phospholipid content, a 9.5-fold increase in mixed lecithin content, a 10.5-fold increase in disaturated phosphatidylcholine content, and a 5.6-fold increase in phosphatidylglycerol content of the tracheal fluid (all P less than 0.001). In the glucose-treated fetuses there were no significant changes in the tracheal fluid SAM flux and phospholipid content following cortisol administration. In lung wash from the control fetuses treated with cortisol there was 8.9-fold more SAM, and on thin-layer chromatography there was 5.6-fold more total phospholipids, 3.9-fold more mixed lecithin, 6.2-fold more disaturated phosphatidylcholine, and 2.5-fold more phosphatidylglycerol when compared with lung wash from the glucose-treated fetuses treated with cortisol (all P less than 0.001). Lung volumes at maximal inflation pressure during air pressure-volume studies were 1.8-fold greater in the cortisol-treated control fetuses than in the glucose-treated fetuses, P less than 0.025. Chronic hyperglycemia with secondary hyperinsulinemia inhibits the maturational response of fetal lamb lungs to cortisol. A similar mechanism may operate in utero to increase the incidence of respiratory distress syndrome in infants of diabetic mothers with poor maternal glucose homeostasis. Moreover, on the basis of these data, prenatal treatment of infants of diabetic mothers with corticosteroids might not be expected to enhance fetal lung maturation.
Sex-specific associations between body mass index, waist circumference and the risk of Barrett's oesophagus: a pooled analysis from the international BEACON consortium
Authors: Ai Kubo, Michael Blaise Cook, Nicholas J Shaheen, Thomas L Vaughan, David C Whiteman, Liam Murray, Douglas A Corley
Journal: Gut (2013)

In an elderly male patient with alcohol-related liver disease, who developed episodic confusion and tremor, we found a large extrahepatic portacaval shunt. He had no clinical or laboratory evidence of liver dysfunction except for an elevated serum ammonia level that increased further in response to an ammonium chloride challenge test. Extrahepatic portacaval shunting causing episodic confusion and tremor may occur with alcoholic liver disease without overt liver failure and may require abdominal angiography or a transhepatic portogram to demonstrate the shunt.
A pulsed Doppler echocardiographic method for calculating pulmonary and systemic blood flow in atrial level shunts: validation studies in animals and initial human experience.
Authors: L M Valdes-Cruz, S Horowitz, E Mesel, D J Sahn, D C Fisher, D Larson
Journal: Circulation (1984)

The purpose of this study was to assess the accuracy of a quantitative two-dimensional range-gated Doppler echocardiographic method for estimating systemic and pulmonary flows in an open-chest canine preparation with a variable-sized atrial level shunt mimicking an atrial septal defect. In addition, we also report our initial experience with 10 children who had isolated atrial septal defects and who had pulmonary and systemic flow rations (QP:QS) determined by Doppler echocardiography simultaneously with green dye-shunt calculations in the cardiac catheterization laboratory. Ten mongrel dogs weighing 20 to 30 kg were anesthetized, intubated, and mechanically ventilated. Previously calibrated electromagnetic flow probes were placed around the ascending aorta and main pulmonary artery, and an atrial level shunt was created by inserting one-half inch diameter cannulae into the left and right atrial appendages and connecting both cannulae to 3/4 inch tubing that passed through a previously calibrated extracorporeal mechanical roller pump. This permitted quantitation as well as regulation of shunt size and direction. With each step-by-step variation in shunt magnitude, systemic and pulmonary flows were estimated by Doppler echocardiography and were matched to the simultaneous electromagnetic flowmeter recordings. Doppler-estimated systemic blood flow was obtained by imaging and recording Doppler flow velocities in the ascending aorta with the transducer positioned directly over the vessel. Doppler pulmonary flow was obtained by imaging the main pulmonary artery on the short-axis view and by determining flow velocity with the sample volume placed distal to the pulmonic valve.(ABSTRACT TRUNCATED AT 250 WORDS)
Increased counteracting effect of NOS and NOS on an α-adrenergic rise in total peripheral vascular resistance in spontaneous hypertensive rats
Authors: T BERG
Journal: Cardiovascular Research (2005)

The hypertension in spontaneous hypertensive rats (SHR) may result from a hyperactive sympathetic nervous system or from insufficient bioactive nitric oxide (NO) due to increased oxidative stress. The present investigation aimed to elucidate the balance between these two systems by studying the ability of NO to oppose an adrenergic rise in total peripheral vascular resistance (TPVR).In anesthetized, open-chest SHR and normotensive controls (WKY) on a respirator, blood pressure was recorded in the femoral artery and cardiac output measured by ascending aorta flow. Tyramine infusion (15 min, intravenously) was used to stimulate neuronal noradrenaline release.Tyramine induced an immediate but transient increase in TPVR, which was 4.5 times greater in SHR. After the non-selective NO synthase (NOS) inhibitor (L-NAME: N(omega)-nitro-L-arginine methyl ester), DeltaTPVRimm was 8.6 and 5.3 times increased in SHR and WKY, respectively, and TPVR remained elevated throughout the infusion period. Addition of alpha1-adrenoceptor antagonist (prazosin+L-NAME) abolished the TPVR response to tyramine. Neuronal NOS inhibitor (7-introindazole) increased DeltaTPVRimm only in SHR (2.1 times), and TPVR remained elevated. Inducible NOS inhibitor (1400W), free radical scavenger (tempol), NAD(P)H oxidase inhibitor (apocynin), angiotensin AT1 receptor antagonist (losartan), and ganglion blocker (hexamethonium) had no effect on the tyramine TPVR response in either strain. DeltaTPVR to hexamethonium, prazosin, and L-NAME were greater in SHR than WKY, and hexamethonium reduced DeltaTPVR to L-NAME in SHR only.The alpha1-adrenoceptor TPVR response to endogenous noradrenaline release was increased in SHR. This was not due to reduced bioavailable NO; on the contrary, NO counteraction was greatly increased, derived from endothelial NOS, with an additional role of neuronal NOS not seen in WKY. An influence of oxidative stress on these responses was not detected in either strain. In addition, a central eNOS sympathoinhibitory component appeared to influence baseline TPVR in SHR.
Candida albicans Infection Affords Protection against Reinfection via Functional Reprogramming of Monocytes
Authors: Jessica Quintin, Sadia Saeed, Joost H.A. Martens, Evangelos J. Giamarellos-Bourboulis, Daniela C. Ifrim, Colin Logie, Liesbeth Jacobs, Trees Jansen, Bart-Jan Kullberg, Cisca Wijmenga, Leo A.B. Joosten, Ramnik J. Xavier, Jos W.M. van der Meer, Hendrik G. Stunnenberg, Mihai G. Netea
Journal: Cell Host & Microbe (2012)
Estradiol metabolism in cirrhosis
Authors: Barnett Zumoff, Jack Fishman, T. F. Gallagher, Leon Hellman
Journal: Journal of Clinical Investigation (1968)

Abnormal estrogen metabolism has been found in cirrhosis after administration of intravenous tracers of estradiol-(3)H to 6 patients and 23 healthy controls. The major abnormalities observed involved estrogen metabolites other than the 3 "classic" ones, i.e., estrone (E1), estradiol (E2), and estriol (E3). Urinary recovery of radioactivity was regularly elevated in the patients, to an average of 71% of the dose compared to 51% in normals. This is considered to reflect the component of intrahepatic cholestasis in cirrhosis. The per cent dose recovered as urinary glucosiduronates (42%) was normal in cirrhotics in contrast to impaired glucuronidation of cortisol metabolites in this disease. E1 and E2 were present in normal amounts, and E3 was slightly elevated to 21% of the extract compared to 14% in controls. There were strikingly decreased excretion of 2-hydroxyestrone (3% compared with normal 20%) and 2-methoxyestrone (2% compared with 5%) and increased excretion of 16alpha-hydroxyestrone (12% compared with normal 6%). Thus cirrhosis, too, is characterized by the reciprocal relationship between decreased 2-hydroxylation and increased 16alpha-hydroxylation previously described in hypothyroidism and male breast cancer. However, unlike these latter, the increase of 16alpha-hydroxy metabolites was less than the decrease of 2-hydroxy metabolites. The data indicate clearcut impairment of 2-hydroxylation, suggestive impairment of 16alpha-hydroxylation, and a definite depression of the reaction 16alpha-hydroxyestrone-->estriol, the latter finding so far unique to cirrhosis. Demonstration of abnormal peripheral metabolism of estrogen in cirrhosis provides a new approach to the origin of the hyperestrogenic syndrome in this disease.