tbuckley/cabot-search huggingface dataset:
The Gut Microbial Endocrine Organ: Bacterially Derived Signals Driving Cardiometabolic Diseases
Authors: J. Mark Brown, Stanley L. Hazen
Journal: Annual Review of Medicine (2015)

The human gastrointestinal tract is home to trillions of bacteria, which vastly outnumber host cells in the body. Although generally overlooked in the field of endocrinology, gut microbial symbionts organize to form a key endocrine organ that converts nutritional cues from the environment into hormone-like signals that impact both normal physiology and chronic disease in the human host. Recent evidence suggests that several gut microbial-derived products are sensed by dedicated host receptor systems to alter cardiovascular disease (CVD) progression. In fact, gut microbial metabolism of dietary components results in the production of proatherogenic circulating factors that act through a meta-organismal endocrine axis to impact CVD risk. Whether pharmacological interventions at the level of the gut microbial endocrine organ will reduce CVD risk is a key new question in the field of cardiovascular medicine. Here we discuss the opportunities and challenges that lie ahead in targeting meta-organismal endocrinology for CVD prevention.
Hormone Dependency of Chromosome Aberrations Induced by 7,12-Dimethylbenz[a]anthracene in Rat Bone Marrow Cells: Site-Specific Increase by Erythropoietin&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Norifumi Ueda, Taketoshi Sugiyama, Subal C. Chattopadhyay, Keiko Goto-Mimura, Sakan Maeda
Journal: JNCI Journal of the National Cancer Institute (1981)

The frequency of chromosome aberrations (CA) 6 hours after iv injection of 50 mg 7,12-dimethylbenz[a]anthracene (DMBA)/kg was studied in bone marrow cells of the noninbred Long-Evans rat under various hematopoietic conditions. The percentage of metaphase cells with CA was enhanced by anemia and suppressed by polycythemia. The low incidence of CA in polycythemic rats was reversed by 6 U of sheep erythropoietin (EP) injected at the time of DMBA treatment. The interchromosomal and intrachromosomal distribution of CA indicated that hematopoietic stimuli, more specifically EP, greatly enhanced DMBA-induced CA in specific chromosomal regions.
Characterization of Gastrin-Induced Proangiogenic Effects <b> <i>In vivo</i> </b> in Orthotopic U373 Experimental Human Glioblastomas and <b> <i>In vitro</i> </b> in Human Umbilical Vein Endothelial Cells
Authors: Florence Lefranc, Tatjana Mijatovic, Véronique Mathieu, Sandrine Rorive, Christine Decaestecker, Olivier Debeir, Jacques Brotchi, Philippe Van Ham, Isabelle Salmon, Robert Kiss
Journal: Clinical Cancer Research (2004)

Abstract Purpose: This study aims to investigate the role of gastrin-17 (G17) on angiogenesis features in gliomas both in vitro and in vivo. Experimental Design: The influences of G17 and G17 receptor antagonists were characterized in vitro in terms of angiogenesis on human umbilical vein endothelial cell (HUVEC) tubulogenesis processes on Matrigel and in vivo with respect to U373 orthotopic glioma xenografts. The influence of phosphatidylinositol 3′-kinase, protein kinase C, and nuclear factor-κB inhibitors was characterized in vitro on G17-mediated HUVEC tubulogenesis. G17-mediated release of interleukin (IL)-8 from HUVECs and G17-induced modifications in nuclear factor-κB DNA binding activity were characterized by means of specific enzyme-linked immunosorbent assays. The influence of G17 on E- and P-selectin expression was determined by means of computer-assisted microscopy, whereas the influence of E- and P-selectin on HUVEC migration was approached by means of antisense oligonucleotides. The chemotactic influence of G17 and IL-8 on HUVEC migration was characterized by means of computer-assisted videomicroscopy with Dunn chambers. Results: Messenger RNAs for cholecystokinin (CCK)A, CCKB, and CCKC receptors were present in HUVECs and microvessels dissected from a human glioblastoma. Whereas G17 significantly increased the levels of angiogenesis in vivo in the U373 experimental glioma model and in vitro in the HUVECs, the CCKB receptor antagonist L365,260 significantly counteracted the G17-mediated proangiogenic effects. G17 chemoattracted HUVECs, whereas IL-8 failed to do so. IL-8 receptor α (CXCR1) and IL-8 receptor β (CXCR2) mRNAs were not detected in these endothelial cells. Gastrin significantly (but only transiently) decreased the level of expression of E-selectin, but not P-selectin, whereas IL-8 increased the expression of E-selectin. Specific antisense oligonucleotides against E- and P-selectin significantly decreased HUVEC tubulogenesis processes in vitro on Matrigel. Conclusions: The present study shows that gastrin has marked proangiogenic effects in vivo on experimental gliomas and in vitro on HUVECs. This effect depends in part on the level of E-selectin activation, but not on IL-8 expression/release by HUVECs.
Static lung volumes in healthy subjects assessed by helium dilution during occlusion of one mainstem bronchus.
Authors: B Johansen, O Bjortuft, J Boe
Journal: Thorax (1993)

BACKGROUND--Single lung function is usually assessed by radioisotopes or, more rarely, by bronchospirometry in which a double lumen catheter is used to separate ventilation of the two lungs. The latter is more precise but less comfortable. An alternative bronchoscopic method is described for determining the volume of a single lung. METHODS--One mainstem bronchus was temporarily occluded with an inflatable balloon during fibreoptic bronchoscopy in 12 healthy volunteers aged 18-29 years. The functional residual capacities (FRC) of the right, left, and both lungs were measured in duplicate by closed circuit helium dilution. Supplementary vital capacity (VC) manoeuvres permitted calculation of single lung capacities (TLC) and residual volumes (RV). RESULTS--The standard deviation of a single determination of capacities of the right, left, and both lungs were: TLC, 80, 96, and 308 ml; VC, 56, 139, 171 ml; FRC, 131, 74, and 287 ml; RV, 112, 185, and 303 ml, respectively. The sum of the right and left unilateral TLC was not different from bilateral TLC (6.12 v 5.95 l) and the sum of the unilateral FRC was not different from the bilateral FRC (2.60 v 2.78 l). The sum of the unilateral VC was lower than bilateral VC (4.52 v 4.80 l), that of the unilateral RV was higher than bilateral RV (1.60 v 1.16 l). For all subdivisions of lung volume, the right lung was larger than the left. The most common complaint was substernal discomfort during complete exhalation. Oxygen saturation rarely fell below 90%. CONCLUSIONS--Temporary occlusion of a mainstem bronchus in normal subjects is safe, relatively simple, and allows fairly precise and accurate measurements of unilateral static lung volumes. Occlusion at TLC, however, probably prevents proper emptying of the non-occluded lung.
Sentinel and Nonsentinel Node Status in Stage IB and II Melanoma Patients: Two-Step Prognostic Indicators of Survival
Authors: Natale Cascinelli, Emilio Bombardieri, Rosaria Bufalino, Tiziana Camerini, Antonino Carbone, Claudio Clemente, Leonardo Lenisa, Luigi Mascheroni, Andrea Maurichi, Elisabetta Pennacchioli, Roberto Patuzzo, Mario Santinami, Gabrina Tragni
Journal: Journal of Clinical Oncology (2006)

To evaluate the prognostic significance of sentinel node biopsy in the management of stage IB and II melanoma patients, and to evaluate the status of nonsentinel nodes as a "second step key factor" to assess the prognosis of these patients.We conducted an analysis of data collected in a prospective database.From February 1994 to June 2005, 1,108 consecutive patients with stage IB and II melanoma were submitted to sentinel node biopsy; 176 patients (15.9%) had occult node metastases. The frequency of positive nodes increased with increasing Breslow's thickness. The largest diameter of metastatic foci and their localization within the lymph node were associated with the risk of nonsentinel node metastases only. The 5-year survival of patients with positive sentinel nodes was 81.4% in patients with one positive node and 39.6% in patients with two positive nodes (P = .056). Multivariate analysis indicated that status of sentinel nodes is a key factor and that sex and Breslow's thickness maintain statistically significant relevance. Ulceration, which was associated with survival when considered as single factor (P < .001) had no impact on survival in the multivariate analysis (P = .10). To evaluate the relevance of metastases to nonsentinel nodes, we identified four groups of patients.Evaluation of the sentinel node is a useful procedure to identify patients to be submitted for complete lymph node dissection. The procedure makes it possible to assess the best prognosis of patients.
Retinoic Acid/Alpha-Interferon Combination Inhibits Growth and Promotes Apoptosis in Mantle Cell Lymphoma through Akt-Dependent Modulation of Critical Targets
Authors: Jessica Dal Col, Katy Mastorci, Damiana Antonia Faè, Elena Muraro, Debora Martorelli, Giorgio Inghirami, Riccardo Dolcetti
Journal: Cancer Research (2012)

Abstract Mantle cell lymphoma (MCL) is characterized by a profound deregulation of the mechanisms controlling cell-cycle progression and survival. We herein show that the combination of 9-cis-retinoic acid (RA) and IFN-α induces marked antiproliferative and proapoptotic effects in MCL cells through the modulation of critical targets. Particularly, IFN-α enhances RA-mediated G0–G1 cell accumulation by downregulating cyclin D1 and increasing p27Kip1 and p21WAF1/Cip1 protein levels. Furthermore, RA/IFN-α combination also induces apoptosis by triggering both caspases-8 and -9 resulting in Bax and Bak activation. In particular, RA/IFN-α treatment downregulates the antiapoptotic Bcl-xL and Bfl-1 proteins and upregulates the proapoptotic BH3-only Noxa protein. Sequestration of Mcl-1 and Bfl-1 by upregulated Noxa results in the activation of Bid, and the consequent induction of apoptosis is inhibited by Noxa silencing. Noxa upregulation is associated with nuclear translocation of the FOXO3a transcription factor as consequence of RA/IFN-α–induced Akt inhibition. Pharmacologic suppression of Akt, but not of TORC1, increases Noxa protein levels and downregulates Bfl-1 protein supporting the conclusion that the inhibition of the Akt pathway, the resulting FOXO3a activation and Noxa upregulation are critical molecular mechanisms underlying RA/IFN-α—dependent MCL cell apoptosis. These results support the potential therapeutic value of RA/IFN-α combination in MCL management. Cancer Res; 72(7); 1825–35. ©2012 AACR.
Screening for Chronic Kidney Disease: Preventing Harm or Harming the Healthy?
Authors: Maarten W. Taal
Journal: PLoS Medicine (2012)

Advances in understanding the pathogenesis and natural history of diseases as well as developments in medical technology have made it possible to diagnose a large number of diseases at early stages, often in asymptomatic individuals.It is intuitive to believe that earlier diagnosis is beneficial because it creates the opportunity to intervene and prevent progression.This simple paradigm may hold true for some conditions, e.g., hypertension, but, it is increasingly clear that for other diseases early diagnosis may not necessarily be beneficial-e.g., in prostate cancer, since not all cases identified will progress to cause symptoms or premature death.Thus there are calls for health professionals to critically appraise the evidence relating to screening policies, to prevent overdiagnosis (''harming the healthy'') [1].A new systematic review in this week's PLOS Medicine by Justin Echouffo-Tcheugui and Andre Kengne, which examined the evidence base for prediction of chronic kidney disease (CKD) risk and its progression, offers a chance to consider these questions for the clinical management of CKD [2].CKD initially seems to be a disease for which screening to facilitate early diagnosis would be beneficial.CKD is relatively common [3], is asymptomatic until advanced stages, progresses over several years, and leads to end-stage kidney disease (ESKD) as well as several other adverse outcomes [4][5][6][7].Nevertheless, while evidence indicates benefit associated with CKD screening in people with diabetes or hypertension, we are still some way from understanding the best strategy for CKD screening in asymptomatic people without such conditions.In short, will general population screening for CKD be effective in identifying the ''truly ill'' or simply ''harm the healthy''?
Sofosbuvir and Ribavirin for Hepatitis C in Patients With HIV Coinfection
Authors: Mark S. Sulkowski, Susanna Naggie, Jacob Lalezari, Walford Jeffrey Fessel, Karam Mounzer, Margaret Shuhart, Anne F. Luetkemeyer, David Asmuth, Anuj Gaggar, Liyun Ni, Evguenia Svarovskaia, Diana M. Brainard, William T. Symonds, G. Mani Subramanian, John G. McHutchison, Maribel Rodriguez-Torres, Douglas Dieterich
Journal: JAMA (2014)

Treatment of hepatitis C virus (HCV) infection in patients also infected with human immunodeficiency virus (HIV) has been limited due to drug interactions with antiretroviral therapies (ARTs) and the need to use interferon.
Antidepressant Treatment in Bipolar Versus Unipolar Depression
Authors: S. Nassir Ghaemi, Klara J. Rosenquist, James Y. Ko, Claudia F. Baldassano, Nicholas J. Kontos, Ross J. Baldessarini
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: Antidepressant responses were compared in DSM-IV bipolar and unipolar depression. METHOD: The authors analyzed clinical records for outcomes of antidepressant trials for 41 patients with bipolar depression and 37 with unipolar depression, similar in age and sex distribution. RESULTS: Short-term nonresponse was more frequent in bipolar (51.3%) than unipolar (31.6%) depression. Manic switching occurred only in bipolar depression but happened less in patients taking mood stabilizers (31.6% versus 84.2%). Cycle acceleration occurred only in bipolar depression (25.6%), with new rapid cycling in 32.1%. Late response loss (tolerance) was 3.4 times as frequent, and withdrawal relapse into depression was 4.7 times less frequent, in bipolar as in unipolar depression. Mood stabilizers did not prevent cycle acceleration, rapid cycling, or response loss. Modern antidepressants, in general, did not have lower rates of negative outcomes than tricyclic antidepressants. CONCLUSIONS: The findings suggest an unfavorable cost/benefit ratio for antidepressant treatment of bipolar depression.
IL-18 Contributes to Renal Damage after Ischemia-Reperfusion
Authors: Huiling Wu, Melissa L. Craft, Peng Wang, Kate R. Wyburn, Gang Chen, Jin Ma, Brett Hambly, Steven J. Chadban
Journal: Journal of the American Society of Nephrology (2008)

IL-18 is a proinflammatory cytokine produced by macrophages and other cell types present in the kidney during ischemia-reperfusion injury (IRI), but its role in this injury is unknown. Here, compared with wild-type mice, IL-18(-/-) mice subjected to kidney IRI demonstrated better kidney function, less tubular damage, reduced accumulation of neutrophils and macrophages, and decreased expression of proinflammatory molecules that are downstream of IL-18. For determination of the relative contributions of leukocytes and parenchymal cells to IL-18 production and subsequent kidney damage during IRI, bone marrow-chimeric mice were generated. Wild-type mice engrafted with IL-18(-/-) hemopoietic cells showed less kidney dysfunction and tubular damage than IL-18(-/-) mice engrafted with wild-type bone marrow. In vitro, macrophages produced IL-18 mRNA and protein in response to ischemia. These data suggest bone marrow-derived cells are the key contributors to IL-18-mediated effects of renal IRI. Finally, similar to IL-18(-/-) mice, pretreatment of wild-type mice with IL-18-binding protein was renoprotective in this model of IRI. In conclusion, IL-18, derived primarily from cells of bone marrow origin, contributes to the renal damage observed during IRI. IL-18-binding protein may have potential as a renoprotective therapy.
Urokinase and the Urokinase Receptor: Association With In Vitro Invasiveness of Human Bladder Cancer Cell Lines
Authors: M. A. Hudson, L. M. McReynolds
Journal: JNCI Journal of the National Cancer Institute (1997)

Background and Purpose: The plasminogen activators urokinase and tissue plasminogen activator are enzymes that degrade proteins in tissue basement membranes and the extracellular matrix (a biomolecular complex surrounding individual cells in tissues that serves as a barrier between the cells and the vascular and lymph systems). The action of these enzymes allows tumor cells to escape their local environment and metastasize. Plasminogen activator activity can be influenced by the urokinase receptor, which is expressed on the surface of cells, and by the plasminogen activator inhibitors 1 and 2. Because bladder tumors differ in their propensity to invade local areas and distant sites, we studied the expression of both plasminogen activators, the two plasminogen activator inhibitors, and the urokinase receptor in four human bladder cancer cell lines (RT4, 253J, EJ, and T24) to see if there was an association between the expression of these proteins and tumor cell invasiveness in vitro. Methods: The expression of urokinase, tissue plasminogen activator, and the two inhibitors was measured by enzyme-linked immunosorbent assays of serum-free, cellconditioned media (i.e., culture fluids). Cell surface expression of the urokinase receptor was assayed by flow cytometry, using an anti-receptor monoclonal antibody (Mab3936). The invasive capacity of untreated cells and of cells exposed to exogenous, highmolecular- weight urokinase was anaanalyzed by use of Matrigel invasion chambers. Results: The four bladder cancer cell lines demonstrated differential expression of both plasminogen activators and both inhibitors; three of the cell lines (T24, EJ, and 253J) expressed the urokinase receptor. The four cell lines differed in their invasive potential in vitro. Neither expression of tissue plasminogen activator nor production of the inhibitors appeared to influence Matrigel invasion. EJ cells and 253J cells produced the highest levels of urokinase and demonstrated the greatest propensity for invasion; T24 cells, which produced only small amounts of urokinase, exhibited a low invasive potential. Pretreatment of T24 cells with exogenous high-molecular-weight urokinase markedly increased their invasiveness. Similar pretreatment of EJ and 253J cells increased their invasiveness as well. RT4 cells, which lacked urokinase receptor expression but produced moderate amounts of urokinase, were not invasive and did not become so after exposure to exogenous highmolecular- weight urokinase. Binding of Mab3936 to urokinase receptors inhibited Matrigel invasion. Conclusions: To our knowledge, this is the first study demonstrating that bladder tumor cells express the urokinase receptor and that both receptor expression and urokinase expression are required for bladder tumor cell invasion in vitro.
The Pruritus of Cholestasis and the Opioid System
Authors: E. Anthony Jones
Journal: JAMA (1992)

<h3>SELECTED CASE</h3> A year after being told that she had abnormal liver test results, a 52-year-old white woman presented with increasing fatigue, pruritus, diffuse abdominal pain, and jaundice. Although endoscopic retrograde cholangiopancreatography was indicated, a diagnostic laparotomy was undertaken. An intraoperative cholangiogram revealed beading and narrowing of intrahepatic and extrahepatic bile ducts characteristic of primary sclerosing cholangitis. Cholecystectomy, exploration of the common bile duct, and endoscopic dilation of large-duct biliary strictures were performed. During the ensuing 12 months the pruritus became severe. Her entire body itched; she slept poorly and felt like she was "on a cactus bed." She scratched until she bled, but scratching did not relieve the pruritus. Conventional doses and schedules of cholestyramine, hydroxyzine hydrochloride, and ursodeoxycholic acid had failed to provide her with relief and her pruritus was considered to be intractable. When referred to the National Institutes of Health, she was scratching continuously and was
Abnormal Bactericidal, Metabolic, and Lysosomal Functions of Chediak-Higashi Syndrome Leukocytes
Authors: Richard K. Root, Alan S. Rosenthal, Dominic J. Balestra
Journal: Journal of Clinical Investigation (1972)

Phagocytic, antimicrobial, and metabolic functions were studied in leukocytes obtained from three patients with the Chediak-Higashi syndrome (CHS) and compared to normals, individuals, heterozygous for Chediak-Higashi syndrome, and two subjects with chronic granulomatous disease of childhood (CGD). Chediak-Higashi syndrome leukocytes showed normal ingestion of a variety of bacteria, Candida albicans, and polystyrene latex particles. Intracellular destruction was significantly impaired for Staphylococcus aureus, Group D streptococci, and a rough strain of Type II pneumococci over a 2 hr incubation. Killing of Serattia marcescens was consistently delayed at 1 hr whereas that of Escherichia coli and C. albicans appeared normal, unless the incubations were shortened to 20 min. Examination of the rates of killing indicated that the greatest defect occurred in the first 20 min of contact between Chediak-Higashi syndrome cells and bacteria. Separation of Chediak-Higashi syndrome granulocytes from monocytes revealed that the former were most defective in bactericidal activity. After phagocytosis, Chediak-Higashi syndrome granulocytes displayed a normal burst in oxygen consumption and oxidation of glucose-1-14C and glucose-6-14C and formate-14C. Oxidation of glucose-1-14C by non-phagocytizing Chediak-Higashi syndrome granulocytes and monocytes averaged 2-3 times normal, whereas glucose-6-14C and formate-14C oxidation were not significantly increased by resting cells. Iodination of intracellular protein by Chediak-Higashi syndrome leukocytes was significantly increased above normal in both the resting and phagocytizing state. Electron microscopic histochemistry revealed that almost all peroxidase activity was localized to the giant granules in Chediak-Higashi granulocytes, and after bacterial ingestion there was a failure of delivery of peroxidase to many phagosomes. Upon longer incubation more phagosomes acquired peroxidase activity, presumably through a fusion process, although many giant granules remained intact. The contrasting patterns and kinetics of the killing defects and the differing metabolic properties of Chediak-Higashi syndrome and chronic granulomatous disease leukocytes emphasize the pleiomorphic nature of inherited disorders of leukocyte function.