tbuckley/cabot-search huggingface dataset:
One-Unit versus Two-Unit Cord-Blood Transplantation for Hematologic Cancers
Authors: John E. Wagner, Mary Eapen, Shelly Carter, Yanli Wang, Kirk R. Schultz, Donna A. Wall, Nancy Bunin, Colleen Delaney, Paul Haut, David Margolis, Edward Peres, Michael R. Verneris, Mark Walters, Mary M. Horowitz, Joanne Kurtzberg
Journal: New England Journal of Medicine (2014)

Umbilical-cord blood has been used as the source of hematopoietic stem cells in an estimated 30,000 transplants. The limited number of hematopoietic cells in a single cord-blood unit prevents its use in recipients with larger body mass and results in delayed hematopoietic recovery and higher mortality. Therefore, we hypothesized that the greater numbers of hematopoietic cells in two units of cord blood would be associated with improved outcomes after transplantation.Between December 1, 2006, and February 24, 2012, a total of 224 patients 1 to 21 years of age with hematologic cancer were randomly assigned to undergo double-unit (111 patients) or single-unit (113 patients) cord-blood transplantation after a uniform myeloablative conditioning regimen and immunoprophylaxis for graft-versus-host disease (GVHD). The primary end point was 1-year overall survival.Treatment groups were matched for age, sex, self-reported race (white vs. nonwhite), performance status, degree of donor-recipient HLA matching, and disease type and status at transplantation. The 1-year overall survival rate was 65% (95% confidence interval [CI], 56 to 74) and 73% (95% CI, 63 to 80) among recipients of double and single cord-blood units, respectively (P=0.17). Similar outcomes in the two groups were also observed with respect to the rates of disease-free survival, neutrophil recovery, transplantation-related death, relapse, infections, immunologic reconstitution, and grade II-IV acute GVHD. However, improved platelet recovery and lower incidences of grade III and IV acute and extensive chronic GVHD were observed among recipients of a single cord-blood unit.We found that among children and adolescents with hematologic cancer, survival rates were similar after single-unit and double-unit cord-blood transplantation; however, a single-unit cord-blood transplant was associated with better platelet recovery and a lower risk of GVHD. (Funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; ClinicalTrials.gov number, NCT00412360.).
Vincristine Induces Dramatic Lysosomal Changes and Sensitizes Cancer Cells to Lysosome-Destabilizing Siramesine
Authors: Line Groth-Pedersen, Marie Stampe Ostenfeld, Maria Høyer-Hansen, Jesper Nylandsted, Marja Jäättelä
Journal: Cancer Research (2007)

Abstract Vincristine is a microtubule-destabilizing antimitotic drug that has been used in cancer therapy for over 40 years. However, the knowledge on vincristine-induced cell death pathways is still sparse. Here, we show that vincristine induces dramatic changes in the lysosomal compartment and sensitizes cells to lysosomal membrane permeabilization. In HeLa cervix carcinoma cells, vincristine induced mitotic arrest and massive cell death associated with an early increase in the lysosomal volume and lysosomal leakage followed by the activation of the intrinsic apoptosis program. In contrast, the majority of vincristine-treated MCF-7 breast carcinoma cells resisted apoptosis. Instead, they adapted to the spindle assembly checkpoint and escaped the mitotic arrest as micronucleated and senescent cells with an increase in the volume and the activity of their lysosomal compartment. Consistent with its substantial effects on the lysosomes, vincristine greatly sensitized cultured cancer cells as well as orthotopic breast cancer xenografts in mice to the cytotoxicity induced by siramesine, a sigma-2 receptor ligand that kills cancer cells by destabilizing their lysosomes. Importantly, the combination of nontoxic concentrations of vincristine and siramesine resulted in massive cell death even in MCF-7 cells that were capable of escaping vincristine-induced spindle assembly checkpoint and cell death. Similar synergism was observed when siramesine was combined with a semisynthetic vincristine analogue, vinorelbine, or with microtubule-stabilizing paclitaxel. These data strongly suggest that combination therapies consisting of microtubule-disturbing and lysosome-destabilizing drugs may prove useful in the treatment of otherwise therapy-resistant human cancers. [Cancer Res 2007;67(5):2217–25]
Regulation of erythropoietin production in a case of congenital erythropoietin‐dependent pure erythrocytosis
Authors: Caterina Borgna‐Pignatti, Nicola Lucio Liberato, Pierluigi Marradi, Vittorio Rosti, Giovanni Barosi
Journal: American Journal of Hematology (1994)

In a patient with congenital erythropoietin-dependent pure erythrocytosis (EDPE) associated with hypersensitivity of erythroid progenitor cells to erythropoietin (Epo), the investigations planned to elucidate the mechanism responsible for hormone hyperproduction revealed that Epo synthesis was (1) independent of normal oxygen-mediated feedback induced by phlebotomy; (2) not modulated by adenosine as a second messenger (the treatment with the adenosine antagonist theophylline in fact left unchanged the serum Epo levels); and (3) uninfluenced by iron therapy. The Epo dose-response curve for growth of erythroid progenitor was similar to that of three age-matched thalassemia patients with increased serum Epo levels, (sEpo) suggesting that the observed erythroid progenitors hypersensitivity to Epo could represent an ex vivo artifact induced by the increased sEpo levels.
Author's response:<i>Helicobacter pylori</i>eradication and gastric cancer prevention
Authors: Peter Malfertheiner
Journal: Gut (2013)

Dr Zhu Wang and coauthors write a critical note regarding the important issue of Helicobacter pylori eradication aiming at the prevention of gastric cancer and challenge the statement made in the Maastricht IV–Florence Consensus Report.

The statement in the Maastricht IV–Florence Consensus Report intends to drive actions against gastric cancer by using H. pylori eradication as there are few beneficial alternative strategies.

Gastric cancer is detected in most cases in advanced and non-curable stages. Screening strategies based on radiography, upper gastrointestinal endoscopy and serum pepsinogens for detection of early gastric cancer with the chance for cure have successfully been adopted so far only in Japan and Korea.2–4

There are several arguments for adopting a screen-and-treat strategy with its potential to prevent gastric cancer.

H. pylori is the key trigger in the multifactorial complexity of gastric cancer based on direct and indirect evidences that include results from epidemiological and basic research studies as well as from clinical observations and …
Can Angiotensin II Type 2 Receptors Have Deleterious Effects in Cardiovascular Disease?
Authors: Bernard I. Lévy
Journal: Circulation (2004)

T he renin-angiotensin system (RAS) plays a major role in regulating the cardiovascular system, and disorders of the RAS contribute largely to the pathophysiology of hypertension, renal diseases, and chronic heart failure.Two subtypes of angiotensin II (Ang II) receptors have been defined on the basis of their differential pharmacological and biochemical properties: Ang II type 1 receptors (AT 1 ), which are involved in most of the well-known physiological effects of Ang II, and Ang II type 2 receptors (AT 2 ), which have a less well-defined role but appear capable of counterbalancing some of the effects of AT 1 stimulation.The 2 receptors, both of which belong to the superfamily of G-protein-coupled receptors, are believed to have different signaling pathways and different functions. 1AT 1 transactivates growth pathways and mediates major Ang II effects such as vasoconstriction, increased cardiac contractility, renal tubular sodium reabsorption, cell proliferation, vascular and cardiac hypertrophy, inflammatory responses, and oxidative stress.AT 2 is believed to induce essentially opposite effects, including vasodilation and antigrowth and antihypertrophic effects, 1-3 and to play a significant role in blood pressure (BP) regulation. 4he 2 major pharmacological inhibitors of the RAS, which are now important elements in the treatment of hypertension and cardiovascular disease, are ACE inhibitors and angiotensin receptor blockers (ARBs).These 2 classes of drugs have different effects on the RAS: suppression of Ang II production by ACE inhibitors reduces activation of both Ang II receptor subtypes, whereas ARBs preferentially block AT 1 and leave AT 2 unopposed.Long-term administration of ARBs results in a several-fold increase in plasma Ang and thus a possible overstimulation of AT 2 .It is generally accepted that the effects of stimulation of AT 2 on the cardiovascular system are beneficial and that no harm would result from increased activation of these receptors; indeed, activation of AT 2 is believed to contribute to the benefits of blocking AT 1 .However, it was difficult to distinguish exactly which of the beneficial effects observed with ARBs arise from a fall in BP and which are due to activation of AT 2 .Recent work has attempted to unravel the receptor typedependent effects by using selective AT 2 antagonists or agonists or mice that have been genetically modified so that they either lack the gene coding for AT 2 or overexpress it.The results of this work often appear to be conflicting, but some of the evidence suggests that activation of AT 2 could, in certain contexts, exert growth stimulatory and proinflammatory effects that result in parallel, rather than opposite, effects to AT 1 stimulation.This article will attempt to briefly review the evidence on the cardiovascular role of AT 2 and to discuss possible implications of overstimulation of these receptors in long-term ARB therapy.
Regulation of Intestinal Lipid Absorption by Clock Genes
Authors: M. Mahmood Hussain
Journal: Annual Review of Nutrition (2014)

Plasma levels of triacylglycerols and diacylglycerols, the lipoproteins that transport them, and proteins involved in their absorption from the intestinal lumen fluctuate in a circadian manner. These changes are likely controlled by clock genes expressed in the intestine that are probably synchronized by neuronal and humoral signals from the suprachiasmatic nuclei, which constitute a master clock entrained by light signals from the eyes and from the environment, e.g., food availability. Acute changes in circadian rhythms—e.g., due to nonsynchronous work schedules or a transcontinental flight—may trigger intestinal discomfort. Chronic disruptions in circadian control mechanisms may predispose the individual to irritable bowel syndrome, gastroesophageal reflux disease, and peptic ulcer disease. A more detailed understanding of the molecular mechanisms underlying temporal changes in intestinal activity might allow us to identify novel targets for developing therapeutic approaches to these disorders.
Memory Enhancement and Deep-Brain Stimulation of the Entorhinal Area
Authors: Nanthia Suthana, Zulfi Haneef, John Stern, Roy Mukamel, Eric Behnke, Barbara Knowlton, Itzhak Fried
Journal: New England Journal of Medicine (2012)

The medial temporal structures, including the hippocampus and the entorhinal cortex, are critical for the ability to transform daily experience into lasting memories. We tested the hypothesis that deep-brain stimulation of the hippocampus or entorhinal cortex alters memory performance.We implanted intracranial depth electrodes in seven subjects to identify seizure-onset zones for subsequent epilepsy surgery. The subjects completed a spatial learning task during which they learned destinations within virtual environments. During half the learning trials, focal electrical stimulation was given below the threshold that elicits an afterdischarge (i.e., a neuronal discharge that occurs after termination of the stimulus).Entorhinal stimulation applied while the subjects learned locations of landmarks enhanced their subsequent memory of these locations: the subjects reached these landmarks more quickly and by shorter routes, as compared with locations learned without stimulation. Entorhinal stimulation also resulted in a resetting of the phase of the theta rhythm, as shown on the hippocampal electroencephalogram. Direct hippocampal stimulation was not effective. In this small series, no adverse events associated with the procedure were observed.Stimulation of the entorhinal region enhanced memory of spatial information when applied during learning. (Funded by the National Institutes of Health and the Dana Foundation.).
Pancreatic stellate cells contribute to regeneration early after acute necrotising pancreatitis in humans
Authors: A Zimmermann
Journal: Gut (2002)

The aim of this study was to systematically analyse the pattern of regeneration in human acute pancreatitis by testing whether pancreatic stellate cells, their myofibroblastic offspring, and pancreatic ductules are involved in the regenerative process.Between January 1994 and November 2000, 24 necrosectomy specimens containing vital tissue were obtained for pathological examination. Formalin fixed tissue samples were routinely processed and immunostained for cytokeratins 7 and 19, smooth muscle actin, desmin, Ki-67, and CD68. Pancreatic tissue from organ donors served as normal controls.Necrosectomy specimens were obtained between 11 and 41 days after the onset of symptoms. In vital areas of necrosectomy samples, spherical hypercellular spheres consisting of loose vascular connective tissue occurred, in part showing duct-like profiles which sprouted from remnant exocrine tissue almost perpendicular to the periphery of the spheres. In normal tissue, only a few stellate cells and myofibroblasts were present around ducts and ductules. In contrast, numerous stellate cells and myofibroblasts were detected in the hypercellular regenerative spheres after acute pancreatitis, both being situated within the loose tissue and forming compact periductular sheaths. Stellate cells/myofibroblasts and ductule cells exhibited increased proliferative activity.Pancreatic stellate cells and their activated myofibroblastic offspring may participate in regeneration after acute necrotising pancreatitis in humans. Time course studies are needed to further strengthen this regeneration concept.
Nanoparticles Complexed with Gene Vectors to Promote Proliferation of Human Vascular Endothelial Cells
Authors: Qian Li, Changcan Shi, Wencheng Zhang, Marc Behl, Andreas Lendlein, Yakai Feng
Journal: Advanced Healthcare Materials (2015)

Amphiphilic block copolymers containing biodegradable hydrophobic segments of depsipeptide based copolymers have been synthesized and explored as gene carriers for enhancing proliferation of endothelial cells in vitro. These polymers form nanoparticles (NPs) with positive charges on their surface, which could condense recombinant plasmids of enhanced green fluorescent protein plasmid and ZNF580 gene (pEGFP‐ZNF580) and protect them against DNase I. ZNF580 gene is efficiently transported into EA.hy926 cells to promote their proliferation, whereby the transfection efficiency of NPs/pEGFP‐ZNF580 is approximately similar to that of Lipofectamine 2000. These results indicate that the NPs might have potential as a carrier for pEGFP‐ZNF580, which could support endothelialization of cardiovascular implants.
CDX2 autoregulation in human intestinal metaplasia of the stomach: impact on the stability of the phenotype
Authors: R. Barros, L. T. da Costa, J. Pinto-de-Sousa, I. Duluc, J.-N. Freund, L. David, R. Almeida
Journal: Gut (2010)

<h3>Background and aims</h3> Intestinal metaplasia (IM) is a gastric preneoplastic lesion that appears following <i>Helicobacter pylori</i> infection and confers an increased risk for development of cancer. It is induced by gastric expression of the intestine-specific transcription factor CDX2. The regulatory mechanisms involved in triggering and maintaining gastric CDX2 expression have not been fully elucidated. The Cdx2<sup>+/−</sup> mouse develops intestinal polyps with gastric differentiation and total loss of Cdx2 expression in the absence of structural loss of the second allele, suggesting a regulatory defect. This putative haplo-insufficiency, together with the apparent stability of IM, led to the hypothesis that CDX2 regulates its own expression through an autoregulatory loop in both contexts. <h3>Methods</h3> Gastrointestinal cell lines were co-transfected with wild-type or mutated Cdx2 promoter constructs and CDX2 expression vector for luciferase assays. Transfection experiments were also used to assess endogenous CDX2 autoregulation, evaluated by RT-PCR, qPCR and western blotting. Chromatin immunoprecipitation was performed in a cell line, mouse ileum and human IM. <h3>Results</h3> CDX2 binds to and transactivates its own promoter and positively regulates its expression in gastrointestinal human carcinoma cell lines. Furthermore, CDX2 is bound to its promoter in the mouse ileum and in human gastric IM, providing a major contribution to understanding the relevance of this autoregulatory pathway in vivo. <h3>Conclusion</h3> The results of this study demonstrate another layer of complexity in CDX2 regulation by an effective autoregulatory loop which may have a major impact on the stability of human IM, possibly resulting in the inevitable progression of the gastric carcinogenesis pathway.
Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial
Authors: S. K. James, M. T. Roe, C. P. Cannon, J. H. Cornel, J. Horrow, S. Husted, H. Katus, J. Morais, P. G. Steg, R. F. Storey, S. Stevens, L. Wallentin, R. A. Harrington
Journal: BMJ (2011)

<b>Objective</b> To evaluate efficacy and safety outcomes in patients in the PLATelet inhibition and patient Outcomes (PLATO) trial who at randomisation were planned for a non-invasive treatment strategy. <b>Design</b> Pre-specified analysis of pre-randomisation defined subgroup of prospective randomised clinical trial. <b>Setting</b> 862 centres in 43 countries. <b>Participants</b> 5216 (28%) of 18 624 patients admitted to hospital for acute coronary syndrome who were specified as planned for non-invasive management. <b>Interventions</b> Randomised treatment with ticagrelor (n=2601) versus clopidogrel (2615). <b>Main outcome measurements</b> Primary composite end point of cardiovascular death, myocardial infarction, and stroke; their individual components; and PLATO defined major bleeding during one year. <b>Results</b> 2183 (41.9%) patients had coronary angiography during their initial hospital admission, 1065 (20.4%) had percutaneous coronary intervention, and 208 (4.0%) had coronary artery bypass surgery. Cumulatively, 3143 (60.3%) patients had been managed non-invasively by the end of follow-up. The incidence of the primary end point was lower with ticagrelor than with clopidogrel (12.0% (n=295) <i>v</i> 14.3% (346); hazard ratio 0.85, 95% confidence interval 0.73 to 1.00; P=0.04). Overall mortality was also lower (6.1% (147) <i>v</i> 8.2% (195); 0.75, 0.61 to 0.93; P=0.01). The incidence of total major bleeding (11.9% (272) <i>v</i> 10.3% (238); 1.17, 0.98 to 1.39; P=0.08) and non-coronary artery bypass grafting related major bleeding (4.0% (90) <i>v</i> 3.1% (71); 1.30, 0.95 to 1.77; P=0.10) was numerically higher with ticagrelor than with clopidogrel. <b>Conclusions</b> In patients with acute coronary syndrome initially intended for non-invasive management, the benefits of ticagrelor over clopidogrel were consistent with those from the overall PLATO results, indicating the broad benefits of P2Y12 inhibition with ticagrelor regardless of intended management strategy. <b>Trial registration</b> Clinical trials NCT00391872.
Circca: a Randomised Double Blind Phase Ii Trial of Carboplatin-Paclitaxel Plus Cediranib Versus Carboplatin-Paclitaxel Plus Placebo in Metastatic/Recurrent Cervical Cancer. (Cruk Grant Ref: C1256/A11416)
Authors: P. Symonds, C. Gourley, S. Davidson, C. West, C. Dive, J. Paul, K. Carty, E. McCartney, D. Rai, S. Banerjee, D. Jackson, R. Lord, M. McCormack, E. Hudson, N. Reed, M. Flubacher, P. Jankowska, M. Powell
Journal: Annals of Oncology (2014)
Diet and inequalities in health
Authors: E L Lloyd
Journal: BMJ (1988)

work for reasons similar to those described above.Once more, after pressure from the patients, we reached agreement with the health authority and the community health councils to have two short visiting spells each day-one in the afternoon and one in the early evening.The precise times and duration depend on the ward concerned.We agree that the patient's needs are paramount but not the exclusive consideration.One patient's wishes should not be inflicted on other sick patients in neighbouring beds.The caring professions have a duty to tend their patients, but if this is constantly hindered by the excessive and prolonged presence of visitors we have a duty to consider where the priority lies.
Oxidized Phospholipids Predict the Presence and Progression of Carotid and Femoral Atherosclerosis and Symptomatic Cardiovascular Disease
Authors: Sotirios Tsimikas, Stefan Kiechl, Johann Willeit, Manuel Mayr, Elizabeth R. Miller, Florian Kronenberg, Qingbo Xu, Claes Bergmark, Siegfried Weger, Friedrich Oberhollenzer, Joseph L. Witztum
Journal: Journal of the American College of Cardiology (2006)
Spontaneous rupture of extensor pollicis longus tendon in a kick boxer.
Authors: T W Lloyd, M P Tyler, A H Roberts
Journal: British Journal of Sports Medicine (1998)

A 23 year old male kick boxer presented with a 24 hour history of pain and being unable to extend the interphalangeal joint of the left thumb. There was no history of trauma or any other risk factor for spontaneous rupture of the extensor pollicis longus tendon. On the previous day, he had been doing reverse press ups on the dorsum of his hands with his wrists hyperflexed as part of his training for kick boxing. At operation the extensor pollicis longus tendon was found to be divided at the level of the dorsal tubercle of the radius and was not directly repairable. The treatment was an extensor indicis proprius transfer. We suggest that the cause of the tendon rupture was direct pressure on the dorsal tubercle of the radius sustained while performing reverse press ups.
A novel missense mutation in the myosin binding protein-C gene is responsible for hypertrophic cardiomyopathy with left ventricular dysfunction and dilation in elderly patients
Authors: Tetsuo Konno, Masami Shimizu, Hidekazu Ino, Toru Matsuyama, Masato Yamaguchi, Hidenobu Terai, Kenshi Hayashi, Tomohito Mabuchi, Masaru Kiyama, Kenji Sakata, Tatsumi Hayashi, Masaru Inoue, Tomoya Kaneda, Hiroshi Mabuchi
Journal: Journal of the American College of Cardiology (2003)