tbuckley/cabot-search huggingface dataset:
Role Of Endothelin-1 and Nitric Oxide Bioavailability in Transplant-Related Vascular Injury
Authors: Danny Ramzy, Vivek Rao, Laura C. Tumiati, Ning Xu, Santiago Miriuka, Diego Delgado, Heather J. Ross
Journal: Circulation (2006)

Cyclosporine (CyA) is associated with many side effects, including endothelial dysfunction and transplant vasculopathy (TxV). We previously demonstrated that CyA results in impairment of nitric oxide bioavailability and enhanced sensitivity to endothelin-1 (ET-1). In this study, we evaluated rapamycin (SRL) for its effects on the endothelium.Lewis rats (n = 8) were injected with SRL (1.5 mg/kg), CyA (5 mg/Kg), or saline (Con) intraperitoneally daily for 2-weeks. Thoracic aortic segments were assessed for endothelial-dependent (Edep) and independent (Eind) relaxation after exposure to acetylcholine and sodium nitroprusside by deriving the percent maximum relaxation (Emax). ET-1 plasma levels were also measured. Thoracic aortic expression of endothelial nitric oxide synthase (eNOS), ET(A) and ET(B) receptors (Rc), were determined. Oxidative injury was assessed by changes in 8-isoprostane levels. CyA exposure resulted in lower Edep vasorelaxation compared with control and SRL (Emax: SRL, 58+/-4%; CyA, 24+/-7%; Con, 52+/-8%; P=0.001). No differences in Eind vasorelaxation were seen. CyA exposure also increased sensitivity to ET-1 (% maximum contraction [Cmax]: Con, 211+/-8%; SRL, 230+/-5%; CyA, 259+/-3%; P=0.04). Only SRL treatment reduced ET-1 plasma levels. CyA reduced eNOS expression by 30% and increased ETA Rc expression by 34% compared with both Con and SRL (P=0.02). CyA resulted in higher 8-isoprostane levels (CyA, 50+/-2%; SRL, 3+/-3%; Con, 2+/-5%; P=0.02).CyA results in vascular dysfunction characterized by impairment of Edep vasorelaxation and enhanced sensitivity to vasospasm. SRL did not impair Edep vasorelaxation or increase sensitivity to vasospasm while lowering ET-1 levels and preserving eNOS protein expression. We conclude that SRL is less deleterious to the vasculature than CyA and may prevent TxV by these mechanisms.
Oxygen consumption in subepicardial and subendocardial regions of the canine left ventricle. The effect of experimental acute valvular aortic stenosis.
Authors: J Vinten-Johansen, H R Weiss
Journal: Circulation Research (1980)

Moderate and severe levels of experimental valvular aortic stenosis (VAS) were produced in anesthetized, open-chest dogs to determine the effects of VAS on subepicardial (EPI) and subendocardial (ENDO) blood flow, O2 extraction, and O2 consumption (MVO2). Regional flow was determined by microspheres, and O2 saturation and extraction were analyzed by a three-wavelength absorbance microspectrophotometric method. Left ventricular pressure-volume work increased by 49% in moderate and 135% in severe VAS. The ENDO:EPI flow ratio averaged 1.21 +/- 0.09 in controls and decreased to 0.90 +/- 0.16 in moderate and 0.89 +/- 0.09 in severe VAS, and coronary flow increased by 40% and 58%, respectively. O2 extraction increased with both moderate and severe VAS, with extraction being higher in the ENDO than the EPI. MVO2 increased more in severe VAS than in moderate VAS. The ENDO:EPI MVO2 ratios fell to 1.10 (moderate) and to 0.84 (severe) from 1.44 in controls. We conclude that the O2 supply and consequently the MVO2 became limited in the ENDO relative to that in the EPI by simultaneous limitation of the O2 extraction reserve and the blood flow to this region during the increased O2 requirements imposed by experimentally induced VAS.
Intracortical Distribution of Renal Blood Flow in Hemorrhagic Shock in Dogs
Authors: Alexander Logan, Pedro Jose, Gilbert Eisner, Lawrence Lilienfield, Lawrence Slotkoff
Journal: Circulation Research (1971)

The effect of acute hypotensive hemorrhage on the intracortical distribution of renal blood flow was studied in anesthetized mongrel dogs with radioactive microspheres. In the early stages of shock, when carotid artery manipulation was avoided, outer cortical blood flow fell drastically and juxtamedullary flow was relatively well preserved. Carotid artery cannulation caused a redistribution of blood flow within the kidney even before hemorrhage, presumably by stimulating the carotid sinus reflex. Subsequently, with hemorrhage there was a parallel reduction in outer cortical and juxtamedullary blood flow. 138 Xe washout curves agreed with the microsphere findings. It was concluded that when the carotid artery was not disturbed, juxtamedullary blood flow was selectively preserved in the early stages of acute hypotensive hemorrhage.
PD-1 promotes immune exhaustion by inducing antiviral T cell motility paralysis
Authors: Bernd H. Zinselmeyer, Sara Heydari, Catarina Sacristán, Debasis Nayak, Michael Cammer, Jasmin Herz, Xiaoxiao Cheng, Simon J. Davis, Michael L. Dustin, Dorian B. McGavern
Journal: The Journal of Experimental Medicine (2013)

Immune responses to persistent viral infections and cancer often fail because of intense regulation of antigen-specific T cells—a process referred to as immune exhaustion. The mechanisms that underlie the induction of exhaustion are not completely understood. To gain novel insights into this process, we simultaneously examined the dynamics of virus-specific CD8+ and CD4+ T cells in the living spleen by two-photon microscopy (TPM) during the establishment of an acute or persistent viral infection. We demonstrate that immune exhaustion during viral persistence maps anatomically to the splenic marginal zone/red pulp and is defined by prolonged motility paralysis of virus-specific CD8+ and CD4+ T cells. Unexpectedly, therapeutic blockade of PD-1–PD-L1 restored CD8+ T cell motility within 30 min, despite the presence of high viral loads. This result was supported by planar bilayer data showing that PD-L1 localizes to the central supramolecular activation cluster, decreases antiviral CD8+ T cell motility, and promotes stable immunological synapse formation. Restoration of T cell motility in vivo was followed by recovery of cell signaling and effector functions, which gave rise to a fatal disease mediated by IFN-γ. We conclude that motility paralysis is a manifestation of immune exhaustion induced by PD-1 that prevents antiviral CD8+ T cells from performing their effector functions and subjects them to prolonged states of negative immune regulation.
The role of Clara cell senescence in the pathogenesis of COPD
Authors: Amir Bar-Shai, Adi Sagiv, Ronen Alon, Valery Krizhanovsky
Journal: European Respiratory Journal (2014)

Background: COPD is a chronic inflammatory disease caused by long-term inhalation of noxious particles and gases, such as cigarette smoke. The prevalence of COPD is age dependent, and the link between aging and COPD pathogenesis is strongly supported by numerous studies.One emerging hypothesis suggests that alveolar- and airway- cell senescence is a key factor linking aging lung to COPD, since cellular senescence limits the proliferative capacity necessary for tissue repair and promotes chronic inflammation.Clara cells are progenitor cells of the peripheral airways involved in airway regeneration and immune responses following injury, and have been suggested to play a critical role in COPD progression.However, the specific contribution of Clara cells senescence to this process has been largely overlooked.

Objective and Methods: To investigate the role of Clara cell senescence in the pathogenesis of COPD we have used a genetic approach based on transgenic mice in which p53, a pivotal senescence regulator was specifically knocked-out in Clara cells. Subsequently, these mice were exposed to chronic LPS inhalation and evaluated for senescence induction, lung inflammation and alveolar destruction.

Results: Chronic LPS exposure induced Clara cell senescence as assessed by increased SA-β-GAL activity, whereas the p53 transgenic mice showed an attenuated Clara cell senescence. Attenuated Clara cell senescence resulted in dramatically reduced innate and adaptive immune responses, and in decrease in emphysematous changes.

Conclusions: Clara-cell senescence plays an important role in the pathogenesis of COPD and its impairment by p53 deletion, protects lungs from progressive alveolar destruction, a hallmark of COPD.
Gene expression patterns during adaptation of a helminth parasite to different environmental niches
Authors: Emmitt R Jolly, Chen-Shan Chin, Steve Miller, Mahmoud M Bahgat, KC Lim, Joseph DeRisi, James H McKerrow
Journal: Genome biology (2007)

Schistosome bloodflukes are complex trematodes responsible for 200 million cases of schistosomiasis worldwide. Their life cycle is characterized by a series of remarkable morphological and biochemical transitions between an invertebrate host, an aquatic environment, and a mammalian host. We report a global transcriptional analysis of how this parasite alters gene regulation to adapt to three distinct environments. Utilizing a genomic microarray made of 12,000 45-50-mer oligonucleotides based on expressed sequence tags, three different developmental stages of the schistosome parasite were analyzed by pair-wise comparisons of transcript hybridization signals. This analysis resulted in the identification of 1,154 developmentally enriched transcripts. This study expands the repertoire of schistosome genes analyzed for stage-specific expression to over 70% of the predicted genome. Among the new associations identified are the roles of robust protein synthesis and programmed cell death in development of cercariae in the sporocyst stages, the relative paucity of cercarial gene expression outside of energy production, and the remarkable diversity of adult gene expression programs that reflect adaptation to the host bloodstream and an average lifespan that may approach 10 years.
Smooth Muscle Proliferation and Role of the Prostacyclin (IP) Receptor in Idiopathic Pulmonary Arterial Hypertension
Authors: Emilia Falcetti, Susan M. Hall, Peter G. Phillips, Jigisha Patel, Nicholas W. Morrell, Sheila G. Haworth, Lucie H. Clapp
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Prostacyclin analogs, used to treat idiopathic pulmonary arterial hypertension (IPAH), are assumed to work through prostacyclin (IP) receptors linked to cyclic AMP (cAMP) generation, although the potential to signal through peroxisome proliferator-activated receptor-γ (PPARγ) exists.IP receptor and PPARγ expression may be depressed in IPAH. We wished to determine if pathways remain functional and if analogs continue to inhibit smooth muscle proliferation.We used Western blotting to determine IP receptor expression in peripheral pulmonary arterial smooth muscle cells (PASMCs) from normal and IPAH lungs and immunohistochemistry to evaluate IP receptor and PPARγ expression in distal arteries.Cell proliferation and cAMP assays assessed analog responses in human and mouse PASMCs and HEK-293 cells. Proliferative rates of IPAH cells were greater than normal human PASMCs. IP receptor protein levels were lower in PASMCs from patients with IPAH, but treprostinil reduced replication and treprostinil-induced cAMP elevation appeared normal. Responses to prostacyclin analogs were largely dependent on the IP receptor and cAMP in normal PASMCs, although in IP(-/-) receptor cells analogs inhibited growth in a cAMP-independent, PPARγ-dependent manner. In IPAH cells, antiproliferative responses to analogs were insensitive to IP receptor or adenylyl cyclase antagonists but were potentiated by a PPARγ agonist and inhibited (∼ 60%) by the PPARγ antagonist GW9662. This coincided with increased PPARγ expression in the medial layer of acinar arteries.The antiproliferative effects of prostacyclin analogs are preserved in IPAH despite IP receptor down-regulation and abnormal coupling. PPARγ may represent a previously unrecognized pathway by which these agents inhibit smooth muscle proliferation.
New dementia targets are proposed for GPs in next year's QOF
Authors: A. O'Dowd
Journal: BMJ (2013)

General practitioners will be asked to help ensure that patients with possible dementia are treated more quickly and get help sooner as part of new indicators in the Quality and Outcomes Framework (QOF) for next year.

The National Institute for Health and Care Excellence (NICE), the health and social care guidance body, published its proposed new indicators for next year’s framework on 1 August.1

The institute’s proposed benchmarks for the 2014-15 framework—the voluntary annual incentive scheme that rewards general practices for improvements in the quality of care provided for patients—include 10 new indicators, falling under four broad clinical areas.

These include four on mental health and behavioural conditions and one that deals with the percentage of patients with dementia who have a …
The Selective Class I PI3K Inhibitor CH5132799 Targets Human Cancers Harboring Oncogenic <i>PIK3CA</i> Mutations
Authors: Hiroshi Tanaka, Miyuki Yoshida, Hiromi Tanimura, Toshihiko Fujii, Kiyoaki Sakata, Yukako Tachibana, Jun Ohwada, Hirosato Ebiike, Shino Kuramoto, Keiichi Morita, Yasushi Yoshimura, Toshikazu Yamazaki, Nobuya Ishii, Osamu Kondoh, Yuko Aoki
Journal: Clinical Cancer Research (2011)

The phosphatidylinositol 3-kinase (PI3K) pathway plays a central role in cell proliferation and survival in human cancer. PIK3CA mutations, which are found in many cancer patients, activate the PI3K pathway, resulting in cancer development and progression. We previously identified CH5132799 as a novel PI3K inhibitor. Thus, this study aimed to clarify the biochemical and antitumor activity of CH5132799 and elucidate the correlation between CH5132799 response and genetic alterations in the PI3K pathway.Kinase inhibitory activity was profiled in cell-free assays. A large panel of human breast, ovarian, prostate, and endometrial cancer cell lines, as well as xenograft models, were used to evaluate the antitumor activity of CH5132799, followed by analysis for genetic alterations. Effects on Akt phosphorylation induced by mTORC1 inhibition were tested with CH5132799 and compared with mTORC1 and PI3K/mTOR inhibitors.CH5132799 selectively inhibited class I PI3Ks and PI3Kα mutants in in vitro kinase assays. Tumors harboring PIK3CA mutations were significantly sensitive to CH5132799 in vitro and were remarkably regressed by CH5132799 in in vivo mouse xenograft models. In combination with trastuzumab, tumors disappeared in the trastuzumab-insensitive breast cancer model with the PIK3CA mutation. Moreover, CH5132799 did not reverse a negative feedback loop of PI3K/Akt/mTOR signaling and induced regression against tumors regrown after long-term mTORC1 inhibitor treatment.CH5132799 is a selective class I PI3K inhibitor with potent antitumor activity against tumors harboring the PIK3CA mutations. Prediction of CH5132799 response on the basis of PIK3CA mutations could enable patient stratification in clinical settings.
Response to Letters Regarding Article, “Pulmonary and Systemic Vascular Dysfunction in Young Offspring of Mothers With Preeclampsia”
Authors: Stefano F. Rimoldi, Pierre-Yves Jayet, Emrush Rexhaj, Sébastien Thalmann, Marcos Schwab, Pierre Turini, Céline Sartori-Cucchia, Pascal Nicod, Urs Scherrer, Claudio Sartori, Damian Hutter, Thomas Stuber, Yves Allemann, Carlos Salinas Salmòn, Mercedes Villena
Journal: Circulation (2011)
Cardiovascular Risk Attributable to Diabetes in Southern Brazil
Authors: Leila B. Moreira, Sandra C. Fuchs, Mário Wiehe, Jeruza L. Neyeloff, Rafael V. Picon, Marina B. Moreira, Miguel Gus, Flávio D. Fuchs
Journal: Diabetes Care (2009)

To analyze the effect of diabetes on general and cardiovascular disease (CVD) mortality and morbidity in southern Brazil.A population-based cohort study of 1,091 individuals was conducted. Diabetes was ascertained by medical history. The vital status of 982 individuals and the incidence of events were ascertained during another visit and through hospital records, death certificates, and verbal necropsy with relatives.The mean +/- SD age of participants was 43.1 +/- 17 years, and 55.7% were women. The prevalence of diabetes was 4.2%, and the mean follow-up time was 5.3 +/- 0.07 years. Mortality was 36.3% and 6.6% in participants with or without diabetes, respectively; the incidence of CVD was 20.8% and 3.0%, with an adjusted hazard ratio of 4.4 (95% CI 2.4-7.9). Diabetic population-attributable risk (PAR) for CVD mortality was 10.1% and 13.1% for total CVD.Diabetes is responsible for a large PAR for overall mortality and cardiovascular events in Brazil.
Insulin resistance, adipokines, and oxidative stress in nondiabetic, hypercholesterolemic patients: leptin as an 8-epi-prostaglandin F2α determinant
Authors: Min-Jeong Shin, Jong Ho Lee, Yangsoo Jang, Eunju Park, Jaewon Oh, Ji Hyung Chung, Namsik Chung
Journal: Metabolism (2006)
Abstract 5041: Aspirin acetylates and activates p53 in HT-29 and HCT-116 colon cancer cells
Authors: Lloyd F. Alfonso, Raghavender Chivukula, Srinivasan Marimuthu, Jayarama B. Gunaje
Journal: Cancer Research (2010)

Abstract Increasing evidences from human epidemiological studies, animal models and in vitro experiments suggest that regular use of aspirin may reduce the risk of cancer of the colon; however, the mechanisms are not well understood. Since aspirin's protective effect is mainly observed in epithelial cell types which are more resistant to chemotherapy, an urgent need exists to identify the primary targets and cancer preventive pathways affected by aspirin. We hypothesized that aspirin's anti-cancer effect may involve acetylation of the tumor suppressor protein p53 and modulation of target gene expression. In the present study, we demonstrate that exposure of HT-29 and HCT-116 colon cancer cells to aspirin caused acetylation of p53 at lysine 382 (K382). HT-29 cells harbor a mutant form of p53 (R273H), whereas HCT-116 contain wild type p53. Acetylated p53 was mainly localized to the nucleus. In both cell types aspirin induced acetylation of p53 in a concentration dependent manner, and this was associated with increased p53 DNA binding activity. Consistent with this, we also observed induction of p21, a protein involved in cell cycle arrest as well as Bax, a mitochondrial proapoptotic protein. Aspirin also caused acetylation of bacterially expressed recombinant p53 in vitro, suggesting that it is a non-enzymatic reaction. Our observation that aspirin acetylates p53 leading to induction of target gene expression suggest that its anti-cancer effect may involve activation of the p53 pathway. Since p53 is mutated in nearly 50% of all tumors which leads to loss of its function, our observation also suggests that aspirin may find use in chemotherapy to reactivate mutant p53. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5041.
Learning from preventable deaths: exploring case record reviewers' narratives using change analysis
Authors: Helen Hogan, Frances Healey, Graham Neale, Richard Thomson, Nick Black, Charles Vincent
Journal: Journal of the Royal Society of Medicine (2014)

Objective To determine if applying change analysis to the narrative reports made by reviewers of hospital deaths increases the utility of this information in the systematic analysis of patient harm. Design Qualitative analysis of causes and contributory factors underlying patient harm in 52 case narratives linked to preventable deaths derived from a retrospective case record review of 1000 deaths in acute National Health Service Trusts in 2009. Participants 52 preventable hospital deaths. Setting England. Main outcome measures The nature of problems in care and contributory factors underlying avoidable deaths in hospital. Results The change analysis approach enabled explicit characterisation of multiple problems in care, both across the admission and also at the boundary between primary and secondary care, and illuminated how these problems accumulate to cause harm. It demonstrated links between problems and underlying contributory factors and highlighted other threats to quality of care such as standards of end of life management. The method was straightforward to apply to multiple records and achieved good inter-rater reliability. Conclusion Analysis of case narratives using change analysis provided a richer picture of healthcare-related harm than the traditional approach, unpacking the nature of the problems, particularly by delineating omissions from acts of commission, thus facilitating more tailored responses to patient harm.
Cocarcinogenic effects of alcohol in hepatocarcinogenesis
Authors: F Stickel, D Schuppan, E G Hahn, H K Seitz
Journal: Gut (2002)

Alcohol is a major aetiological factor in hepatocarcinogenesis but our understanding of its importance as a modulating factor is just beginning to emerge. In the present review, a number of possible cofactors and mechanisms are discussed by which alcohol may enhance the development of hepatoma. These include dietary or environmental carcinogens ingested along with alcoholic beverages, alcoholic cirrhosis as a precancerous condition, and the effects of alcohol metabolism.
Dynein light chain binding to a 3′-untranslated sequence mediates parathyroid hormone mRNA association with microtubules
Authors: Eyal Epstein, Alin Sela-Brown, Israel Ringel, Rachel Kilav, Stephen M. King, Sharon E. Benashski, Joel K. Yisraeli, Justin Silver, Tally Naveh-Many
Journal: Journal of Clinical Investigation (2000)

The 3′-untranslated region (UTR) of mRNAs binds proteins that determine mRNA stability and localization. The 3′-UTR of parathyroid hormone (PTH) mRNA specifically binds cytoplasmic proteins. We screened an expression library for proteins that bind the PTH mRNA 3′-UTR, and the sequence of 1 clone was identical to that of the dynein light chain LC8, a component of the dynein complexes that translocate cytoplasmic components along microtubules. Recombinant LC8 binds PTH mRNA 3′-UTR, as shown by RNA electrophoretic mobility shift assay. We showed that PTH mRNA colocalizes with microtubules in the parathyroid gland, as well as with a purified microtubule preparation from calf brain, and that this association was mediated by LC8. To our knowledge, this is the first report of a dynein complex protein binding an mRNA. The dynein complex may be the motor that is responsible for transporting mRNAs to specific locations in the cytoplasm and for the consequent is asymmetric distribution of translated proteins in the cell.
Dynamic neuronal regulatory network during the progression of Alzheimer’s disease suggests an adaptive survival strategy
Authors: Jiya Sun, Xuemei Feng, Dapeng Liang, Yong Duan, Hongxing Lei
Journal: Molecular Neurodegeneration (2012)

Alzheimer’s disease (AD) is the most common neurodegenerative disease. In this work, comprehensive analyses on transcriptome studies of human postmortem brain tissues from AD patients revealed stepwise breakdown of the cellular machinery during the progression of AD at semi-quantitative level. At the early stage of AD, the accumulation of A-beta oligomers and amyloid plaques leads to the down-regulation of biosynthesis and energy metabolism, likely a response to the reduced level of nutrient and oxygen supply. At the intermediate stage, the progression of the disease leads to enhanced signal transduction, also likely an adjustment to the deteriorating environment. The late stage is characterized by the elevated apoptosis due to the excessive regulatory and repair burden. Interestingly, the elevated apoptosis at the late stage is accompanied by elevated anti-apoptotic signals, suggesting an adaptive survival strategy even at the late stage of AD. These findings can serve as theoretical basis for pharmaceutical intervention of Alzheimer’s disease.
The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses
Authors: Mitsutoshi Yoneyama, Mika Kikuchi, Takashi Natsukawa, Noriaki Shinobu, Tadaatsu Imaizumi, Makoto Miyagishi, Kazunari Taira, Shizuo Akira, Takashi Fujita
Journal: Nature Immunology (2004)