tbuckley/cabot-search huggingface dataset:
Impaired Coronary Endothelium–Dependent Vasodilation Is Associated With Microalbuminuria in Patients With Type 2 Diabetes and Angiographically Normal Coronary Arteries
Authors: Emmanuel Cosson, Isabelle Pham, Paul Valensi, Jacques Pariès, Jean-Raymond Attali, Alain Nitenberg
Journal: Diabetes Care (2006)

OBJECTIVE—Microalbuminuria and impaired endothelium-dependent vasodilation are both predictors for cardiac events in patients with type 2 diabetes. The aim of the study was to evaluate whether microalbuminuria correlated with coronary endothelium–dependent vasodilation. RESEARCH DESIGN AND METHODS—We evaluated 84 patients (47 men, mean age 50.5 ± 5.9 years) with type 2 diabetes for 9.4 ± 3.4 years, without angiographic coronary stenosis and without major cardiovascular risk factors or other confounding factors, for endothelium investigation. Quantitative coronary angiography was used to assess coronary artery response to cold pressor testing, used to assess endothelium-dependent vasodilation, and to isosorbide dinitrate (endothelium-independent vasodilation). RESULTS—Endothelium-dependent vasodilation differed in the patients with and without microalbuminuria (changes in coronary artery diameter during cold pressor testing: −15.0 ± 1.9% vs. −10.2 ± 1.3%, respectively, P &amp;lt; 0.05) and correlated with urinary albumin excretion rate (r = −0.39, P = 0.003), diastolic blood pressure (r = 0.29, P &amp;lt; 0.01), and left ventricular mass index (r = −0.24, P &amp;lt; 0.05). Independent predictors for endothelium-dependent vasodilation were urinary albumin excretion rate (β −0.04 [95% CI −0.07 to −0.01], P &amp;lt; 0.005) and left ventricular mass index (−0.26 [−0.49 to −0.05], P &amp;lt; 0.05). Endothelium-independent vasodilation was similar in both groups. CONCLUSIONS—Type 2 diabetic patients with microalbuminuria have a more severely impaired coronary endothelium–dependent vasodilation than those with normoalbuminuria. These data suggest a common pathophysiological process for both coronary vasomotor abnormalities and microalbuminuria.
Conditionally Replicating Adenovirus Expressing TIMP2 for Ovarian Cancer Therapy
Authors: Sherry W. Yang, James J. Cody, Angel A. Rivera, Reinhard Waehler, Minghui Wang, Kristopher J. Kimball, Ronald A. Alvarez, Gene P. Siegal, Joanne T. Douglas, Selvarangan Ponnazhagan
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Current treatments for ovarian cancer have limited therapeutic outcomes due to advanced stage of the disease at diagnosis. Among new therapies, conditionally replicating adenoviruses (CRAds), designed to selectively lyse cancer cells, hold promise. In clinical trials, CRAds exhibited limited efficacy thus far. Second-generation CRAds are being developed to express a therapeutic protein to enhance antitumor efficacy. One attractive target in the tumor microenvironment is the matrix metalloproteinases (MMPs) that degrade the extracellular matrix, and are upregulated in ovarian cancer. Tissue inhibitor of metalloproteinase 2 (TIMP2) is an endogenous inhibitor of MMPs. The present study developed and evaluated a novel CRAd (Ad5/3-CXCR4-TIMP2) for ovarian cancer therapy. Experimental Design: A targeted CRAd, Ad5/3-CXCR4-TIMP2 was developed using the CXCR4 promoter for enhanced replication, and expressing the TIMP2 transgene. The efficacy of this armed CRAd was determined in both established human ovarian cancer cell lines and in primary ovarian tumor samples. Results: Ad5/3-CXCR4-TIMP2 mediated expression of functional TIMP2, as demonstrated by the inhibition of MMP activity. In addition, arming with TIMP2 did not inhibit viral replication or oncolytic potency, as the TIMP2-armed viruses showed enhanced killing of cancer cells when compared to the unarmed viruses. We also examined viral replication in primary ovarian cancer tissues obtained from patients with stage III and IV ovarian cancer. In four of the five tumor samples, Ad5/3-CXCR4-TIMP2 revealed a 21- to 89-fold increase in replication when compared to the Ad5/3 virus. Conclusion: Results support the translational potential of Ad5/3-CXCR4-TIMP2 for treatment of patients with advanced ovarian cancer. Clin Cancer Res; 17(3); 538–49. ©2010 AACR.
Exacerbations and intent-to-treat analyses in randomised trials
Authors: S. Suissa
Journal: European Respiratory Journal (2008)

To the Editors: 

The recent paper by Keene et al. 1 that reviews different approaches for the analysis of exacerbation rates is valuable because of the central role of exacerbations in evaluating the benefits of drugs in chronic obstructive pulmonary disease (COPD) trials 1. The authors present reanalyses of the TRISTAN (Trial of Inhaled Steroids and Long-acting β2-agonists) and ISOLDE (Inhaled Steroids in Obstructive Lung Disease in Europe) trial data, which have been previously identified as incorrectly analysed because of the absence of consideration for between-subject variability in exacerbation rates 2. With the proper reanalyses, their conclusions from these trials remain the same; namely that inhaled corticosteroids (ICSs) with or without long-acting β-agonists reduce the frequency of …
Resonance. The missing phenomenon in hemodynamics.
Authors: Y Y Wang, S L Chang, Y E Wu, T L Hsu, W K Wang
Journal: Circulation Research (1991)

To simulate a short segment of the aorta, we studied wave propagation in an elastic tube with a side branch balloon. The small balloon simulated the organ (group of arterioles). Ligation of this side branch would reduce the moduli of the higher harmonics when the length of the side branch was appropriate. Electrical analogy of vessels was used to analyze this phenomenon. This simulation can explain the ligation results we found in rats. It may also clarify the discrepancies between the prediction of the Womersley equation and the experimental results. We suggest that the aorta and the closely attached organ can produce coupled oscillation; theoretically, this structure is equivalent to a resonance circuit.
RIZ1 is potential CML tumor suppressor that is down-regulated during disease progression
Authors: Ashakumary Lakshmikuttyamma, Naoto Takahashi, Elodie Pastural, Emina Torlakovic, Hesham M Amin, Guillermo Garcia-Manero, Michael Voralia, Magdalena Czader, John F DeCoteau, C Ronald Geyer
Journal: Journal of Hematology & Oncology (2009)

RIZ1 expression and activity are reduced in many cancers. In AML cell lines and patient material, RIZ1 expression is reduced relative to normal bone marrow. In chronic myelogenous leukemia (CML), blastic transformation is associated with loss of heterozygosity in the region where RIZ1 is located. RIZ1 is a PR domain methyltransferase that methylates histone H3 lysine 9, a modification important for transcriptional repression. In CML blast crisis cell lines RIZ1 represses insulin-like growth factor-1 expression and autocrine signaling. Together these observations suggest that RIZ1 may have a role in the chronic phase to blast crisis transition in CML.In CML patient material, we observed that RIZ1 expression was decreased during progression from chronic phase to blast crisis. RIZ1 was expressed in mature myeloid and CD34+ cells demonstrating that decreased RIZ1 expression in blast crisis is not due to an increased immature cell population. Expression of RIZ1 CML blast crisis cell lines decreased proliferation, increased apoptosis, and enhanced differentiation.RIZ1 is a candidate tumor suppressor gene whose expression is decreased in blast crisis. Loss of RIZ1 activity results in decreased apoptosis and differentiation and enhanced proliferation. Together these results suggest that loss of RIZ1 expression will lead to an increase in myeloid blast cell population resulting in CML progression.
Obscure gastrointestinal bleeding occurring 50 years after an appendectomy
Authors: S. Kashima, T. Nata, M. Fujiya, K. Moriichi, Y. Nomura, N. Ueno, K. Itabashi, C. Ishikawa, Y. Inaba, T. Ito, K. Okamoto, Y. Mizukami, Y. Ebisawa, N. Chisato, T. Kohno, Y. Tokusashi, N. Miyokawa, M. Yamada, Y. Kohgo
Journal: Gut (2010)

A 69-year-old male, with a history of an appendectomy 50 years previously, presented to hospital due to refractory dizziness and bloody stool. A routine blood test revealed that he had severe anaemia. Upper and lower endoscopy revealed no evidence of bleeding in the oesophagus, stomach, duodenum, terminal ileum or colorectum. He was diagnosed as having obscure gastrointestinal bleeding.1 Capsule endoscopy (CE) was performed and dark-bluish areas with whitish villi were detected in the jejunum (figure 1). Subsequently, double-balloon endoscopy (DBE) was performed orally and multiple dark-bluish areas coated with whitish villi were found at the distal jejunum (figure 2A), and white debris also oozed from …
The hidden universal distribution of amino acids biosynthetic networks: a genomic perspective on its origins and evolution
Authors: Georgina Hernandez-Montes, J. Javier Diaz-Mejia, Ernesto Perez-Rueda, Lorenzo Segovia
Journal: Genome biology (2008)

Twenty amino acids comprise the universal building blocks of proteins. However, their biosynthetic routes do not appear to be universal from an Escherichia coli-centric perspective. Nevertheless, it is necessary to understand their origin and evolution in a global context, that is, to include more 'model' species and alternative routes in order to do so. We use a comparative genomics approach to assess the origins and evolution of alternative amino acid biosynthetic network branches. By tracking the taxonomic distribution of amino acid biosynthetic enzymes, we predicted a core of widely distributed network branches biosynthesizing at least 16 out of the 20 standard amino acids, suggesting that this core occurred in ancient cells, before the separation of the three cellular domains of life. Additionally, we detail the distribution of two types of alternative branches to this core: analogs, enzymes that catalyze the same reaction (using the same metabolites) and belong to different superfamilies; and 'alternologs', herein defined as branches that, proceeding via different metabolites, converge to the same end product. We suggest that the origin of alternative branches is closely related to different environmental metabolite sources and life-styles among species. The multi-organismal seed strategy employed in this work improves the precision of dating and determining evolutionary relationships among amino acid biosynthetic branches. This strategy could be extended to diverse metabolic routes and even other biological processes. Additionally, we introduce the concept of 'alternolog', which not only plays an important role in the relationships between structure and function in biological networks, but also, as shown here, has strong implications for their evolution, almost equal to paralogy and analogy.
ACUTE DESTRUCTION BY HUMORAL ANTIBODY OF RAT SKIN GRAFTED TO MICE
Authors: Henry J. Winn, Conrad A. Baldamus, Somarie V. Jooste, Paul S. Russell
Journal: The Journal of Experimental Medicine (1973)

A study has been made of the roles played by complement and polymorphonuclear leukocytes (PMN) in the acute destruction of xenografts of rat skin that follows injection of their hosts with antisera specifically reactive with graft antigens. The rat skin was grafted onto mice whose immune responses were suppressed by removal of the thymus and a brief course of treatment with rabbit antimouse lymphocyte serum. At about 2 wk after grafting the mice were injected intravenously or intraperitoneally with mouse antirat serum (MARS). This time interval was chosen because it avoided the complications that might be associated with either the process of healing in or with incipient rejection. Signs of graft damage were evident as early as 10 min after the injection of MARS, and in most animals so injected the grafts were completely destroyed within 24–48 h. The role of complement (C) in this acute destructive process is indicated by the results of three lines of experimentation. (a) Non-C-fixing antibodies or antibody fragments failed to cause damage to the grafts. Indeed, both chicken antirat serum and F(ab')2 fragments from rabbit antirat serum completely protected the grafts against the effects of MARS that was administered 24 h later. (b) When mice were depleted of hemolytic C by treatment with cobra venom factor or heat-aggregated gamma globulin, the damage caused by MARS was greatly reduced or completely inhibited. (c) In mice with a genetically determined absence of C5 much greater quantities of MARS were required to cause graft damage; the tempo of the destructive process was consistently slower; and a greater number of grafts recovered from the initial inflammatory process than was the case for animals with an intact complement system. The participation of PMN in serum-mediated destruction of grafts was initially suggested by the results of microscope examination of fixed tissues. The essential role of these cells in the process is indicated by the failure of MARS to cause tissue damage in mice whose circulating PMN have been reduced to very low levels by treatment with nitrogen mustard or more specifically with an anti-PMN serum. The absence of tissue damage when circulating PMN are reduced but C levels are normal suggests that C-mediated cytolysis is unimportant in graft destruction and that the role of C lies in its ability to generate chemotactic factors. The latter may then attract the PMN that provide mediators of tissue damage.
Molecular Basis of Angiopathy in Diabetes Mellitus
Authors: Jean-Sébastien Silvestre, Bernard I. Lévy
Journal: Circulation Research (2006)

ardiovascular complications are the leading cause of morbidity and mortality in patients with diabetes mellitus; up to 80% of deaths in patients with diabetes are closely associated with vascular disease.The ability of the organism to form a collateral network of blood vessels constitutes an important response to vascular occlusive disease and determines to a large part the clinical consequences and severity of tissue ischemia.The development of new vessels is significantly reduced in diabetic patients with coronary or peripheral artery disease. 1,2This probably contributes to the severe course of limb ischemia in diabetic patients, in which peripheral artery disease often results in foot ulceration and lower extremity amputation.Diabetic retinopathy remains one of the major causes of acquired blindness in developed nations.This is true despite the development of laser treatment, which can prevent blindness in the majority of those who develop macular edema or proliferative diabetic retinopathy.The hallmark of diabetic retinopathy is the lack of microvessels in the macula, leading to hypoxia, associated with peripheral retinal neovascularization that may ultimately cause severe vitreous cavity bleeding and/or retinal detachment.The factors that stimulate retinal blood vessel growth have not been fully defined, but there is accumulating evidence that the renin-angiotensin-bradykinin system (RAKS) may be involved in a number of retinal vascular disorders, including retinopathy of prematurity and proliferative diabetic retinopathy 3,4 Only a few studies have specifically evaluated the effect of diabetes on angiogenesis in ischemic vascular disease and in the retina.Moreover, the mechanisms by which diabetes could both limit the formation of new blood vessels in most organs and simultaneously induce proliferative diabetic retinopathy remain largely undefined.
Fitness Trade-Offs Determine the Role of the Molecular Chaperonin GroEL in Buffering Mutations
Authors: Beatriz Sabater-Muñoz, Maria Prats-Escriche, Roser Montagud-Martínez, Adolfo López-Cerdán, Christina Toft, José Aguilar-Rodríguez, Andreas Wagner, Mario A. Fares
Journal: Molecular Biology and Evolution (2015)

Molecular chaperones fold many proteins and their mutated versions in a cell and can sometimes buffer the phenotypic effect of mutations that affect protein folding. Unanswered questions about this buffering include the nature of its mechanism, its influence on the genetic variation of a population, the fitness trade-offs constraining this mechanism, and its role in expediting evolution. Answering these questions is fundamental to understand the contribution of buffering to increase genetic variation and ecological diversification. Here, we performed experimental evolution, genome resequencing, and computational analyses to determine the trade-offs and evolutionary trajectories of Escherichia coli expressing high levels of the essential chaperonin GroEL. GroEL is abundantly present in bacteria, particularly in bacteria with large loads of deleterious mutations, suggesting its role in mutational buffering. We show that groEL overexpression is costly to large populations evolving in the laboratory, leading to groE expression decline within 66 generations. In contrast, populations evolving under the strong genetic drift characteristic of endosymbiotic bacteria avoid extinction or can be rescued in the presence of abundant GroEL. Genomes resequenced from cells evolved under strong genetic drift exhibited significantly higher tolerance to deleterious mutations at high GroEL levels than at native levels, revealing that GroEL is buffering mutations in these cells. GroEL buffered mutations in a highly diverse set of proteins that interact with the environment, including substrate and ion membrane transporters, hinting at its role in ecological diversification. Our results reveal the fitness trade-offs of mutational buffering and how genetic variation is maintained in populations.
Importance of anti- and pro-nociceptive mechanisms in human disease
Authors: I Tracey
Journal: Gut (2004)

Abnormalities in endogenous descending pain inhibitory and facilitatory influences probably contribute to the development and maintenance of chronic pain states

The burden of chronic pain to society is enormous. This is both in terms of physical and emotional impact to individuals and carers, in addition to the large financial burden. Current estimates suggest that 11.5–55.2% of individuals worldwide are defined as suffering from chronic widespread pain.1 A major characteristic of functional disorders such as irritable bowel syndrome (IBS) and inflammatory/neuropathic disorders such as gastro-oesophageal reflux and chronic pancreatitis is abdominal discomfort or pain. There is an increasing awareness that many similarities exist mechanistically between somatic chronic pain conditions and the pain witnessed as chronic in IBS and chronic pancreatitis patients. With this realisation there has been a change of focus for researchers of both somatic and visceral pain conditions from peripheral structures as the preferred target of research to the central nervous system (CNS). It has long been recognised that the CNS has a major modulating nociceptive influence that alters resultant pain perception.2–4 Recent developments in neuroimaging have enabled CNS investigations of visceral pain processing in patients and controls and such studies have highlighted the additional relevance of cognitive and emotional factors in modulating pain perception from physical changes such as plasticity and sensitisation.5–7 Imaging studies have provided valuable objective information on what is inherently a subjective phenomenon, that for too long has relied upon patients giving a self report of their pain using coarse pain rating scales.8 Currently, there is a wider imaging literature on pain processing from somatic structures compared with visceral organs. This is probably because it is experimentally (and ethically) easier to perform somatic acute pain paradigms in healthy controls (for instance, using noxious thermal events) compared with more challenging …
Ablative Tumor Radiation Can Change the Tumor Immune Cell Microenvironment to Induce Durable Complete Remissions
Authors: Alexander Filatenkov, Jeanette Baker, Antonia M.S. Mueller, Justin Kenkel, G-One Ahn, Suparna Dutt, Nigel Zhang, Holbrook Kohrt, Kent Jensen, Sussan Dejbakhsh-Jones, Judith A. Shizuru, Robert N. Negrin, Edgar G. Engleman, Samuel Strober
Journal: Clinical Cancer Research (2015)

Abstract Purpose: The goals of the study were to elucidate the immune mechanisms that contribute to desirable complete remissions of murine colon tumors treated with single radiation dose of 30 Gy. This dose is at the upper end of the ablative range used clinically to treat advanced or metastatic colorectal, liver, and non–small cell lung tumors. Experimental Design: Changes in the tumor immune microenvironment of single tumor nodules exposed to radiation were studied using 21-day (&amp;gt;1 cm in diameter) CT26 and MC38 colon tumors. These are well-characterized weakly immunogenic tumors. Results: We found that the high-dose radiation transformed the immunosuppressive tumor microenvironment resulting in an intense CD8+ T-cell tumor infiltrate, and a loss of myeloid-derived suppressor cells (MDSC). The change was dependent on antigen cross-presenting CD8+ dendritic cells, secretion of IFNγ, and CD4+T cells expressing CD40L. Antitumor CD8+ T cells entered tumors shortly after radiotherapy, reversed MDSC infiltration, and mediated durable remissions in an IFNγ-dependent manner. Interestingly, extended fractionated radiation regimen did not result in robust CD8+ T-cell infiltration. Conclusions: For immunologically sensitive tumors, these results indicate that remissions induced by a short course of high-dose radiotherapy depend on the development of antitumor immunity that is reflected by the nature and kinetics of changes induced in the tumor cell microenvironment. These results suggest that systematic examination of the tumor immune microenvironment may help in optimizing the radiation regimen used to treat tumors by adding a robust immune response. Clin Cancer Res; 21(16); 3727–39. ©2015 AACR.
Prevalence of paraneoplastic hyperthyroidism in patients with metastatic non-seminomatous germ-cell tumors
Authors: S.F. Oosting, E.C. de Haas, T.P. Links, D. de Bruin, W.J. Sluiter, I.J. de Jong, H.J. Hoekstra, D.T. Sleijfer, J.A. Gietema
Journal: Annals of Oncology (2009)
Prevalence and impact of unrecognized COPD on elective surgery
Authors: Jill Ohar, Angela Edwards, Suzanne Howard, Mathew Benshoff, James Donohue
Journal: European Respiratory Journal (2012)

Surgery patients with COPD have more episodes of post op bronchitis, pneumonia and longer length of stays (Manganas H 2007). NHANES data shows that less than 50% of patients with COPD are recognized. It is assumed that unrecognized COPD is less severe and therefore does not significantly affect perioperative morbidity.  We aimed to determine the prevalence and effect of undiagnosed COPD on perioperative morbidity measured by hospital length of stay (LOS), in a population selected for COPD risk.  Spirometry was performed in an at risk population (≥ 40 y.o. with a smoking history ≥ 20 pack-years) scheduled for elective surgery, during preoperative assessment (Ohar J 2011). Obstruction was defined by an FEV1/FVC   Of the 199 subjects tested, 79 (40%) met spirometric criteria for obstruction. Only 9 of the 79 (11%) were previously recognized. Subjects with previously recognized COPD were older (75±8 v. 66±10 y.o.; p   Conclusion:  The prevalence of unrecognized COPD among surgical patients is quite high and it appears to affect perioperative morbidity similarly to previously recognized COPD. The data suggests that spirometric testing of an at risk population for COPD may have value in preoperative assessment.