tbuckley/cabot-search huggingface dataset:
Lentiviral gene transfer and ex vivo expansion of human primitive stem cells capable of primary, secondary, and tertiary multilineage repopulation in NOD/SCID mice
Authors: Wanda Piacibello, Stefania Bruno, Fiorella Sanavio, Sara Droetto, Monica Gunetti, Laurie Ailles, Francesca Santoni de Sio, Andrea Viale, Loretta Gammaitoni, Angelo Lombardo, Luigi Naldini, Massimo Aglietta
Journal: Blood (2002)
Cholesterol requirement of P3-X63-Ag8 and X63-Ag8.653 mouse myeloma cells for growth in vitro.
Authors: J D Sato, T Kawamoto, T Okamoto
Journal: The Journal of Experimental Medicine (1987)

P3-X63-Ag8 and X63-Ag8.653 mouse myeloma cells have an absolute requirement for cholesterol for growth under serum-free conditions. This requirement can be satisfied by low density lipoprotein at 2-6 micrograms/ml or by BSA-bound cholesterol at 5-10 micrograms/ml. Cholesterol-independent variants can be selected after prolonged growth in low concentrations of serum.
Glioblastoma Angiogenesis and Tumor Cell Invasiveness Are Differentially Regulated by β8 Integrin
Authors: Jeremy H. Tchaicha, Steve B. Reyes, Jaekyung Shin, Mohammad G. Hossain, Frederick F. Lang, Joseph H. McCarty
Journal: Cancer Research (2011)

Abstract Glioblastoma multiforme (GBM) is a highly invasive brain tumor that develops florid microvascular proliferation and hemorrhage. However, mechanisms that favor invasion versus angiogenesis in this setting remain largely uncharacterized. Here, we show that integrin β8 is an essential regulator of both GBM-induced angiogenesis and tumor cell invasiveness. Highly angiogenic and poorly invasive tumors expressed low levels of β8 integrin, whereas highly invasive tumors with limited neovascularization expressed high levels of β8 integrin. Manipulating β8 integrin protein levels altered the angiogenic and invasive growth properties of GBMs, in part, reflected by a diminished activation of latent TGFβs, which are extracellular matrix protein ligands for β8 integrin. Taken together, these results establish a role for β8 integrin in differential control of angiogenesis versus tumor cell invasion in GBM. Our findings suggest that inhibiting β8 integrin or TGFβ signaling may diminish tumor cell invasiveness during malignant progression and following antivascular therapies. Cancer Res; 71(20); 6371–81. ©2011 AACR.
BRAFV600E and Microenvironment in Thyroid Cancer: A Functional Link to Drive Cancer Progression
Authors: Carmelo Nucera, Jack Lawler, Sareh Parangi
Journal: Cancer Research (2011)

Abstract Papillary thyroid cancer (PTC) rates continue to increase in the United States and Europe, and, although most patients do well, some recur and die of their disease. Patients with PTC harboring the BRAFV600E mutation seem to display a more aggressive clinical behavior, but little is known about the role of this mutation in crucial processes in the tumor microenvironment, such as tumor adhesion, migration, invasion, and metastasis. The extracellular matrix (ECM) microenvironment is not merely a structural scaffold for the cellular elements of the epithelial and stromal microenvironment, but it also elicits a profound influence on cell behavior affecting viability, proliferation, adhesion, and motility. The effects of BRAFV600E on cell surface receptors (i.e., integrins) and ECM noncellular components [i.e., thrombospondin-1 (TSP-1) and fibronectin (FN)] seem to trigger different pathologic biological processes in a cell context–dependent manner. This review focuses on the recent progress in understanding the role of BRAFV600E in the regulation of some ECM noncellular components and trans-membrane receptors of the microenvironment in PTC in order to design novel targeted therapies directed at the BRAFV600E multifaceted signaling cascades. Some of these targeted therapeutics, such as ATP-competitive BRAFV600E inhibitors (i.e., orally bioavailable PLX4720 and PLX4032 compounds), are already under investigation. Cancer Res; 71(7); 2417–22. ©2011 AACR.
Gntb-A, a Novel Sh2d1a-Associated Surface Molecule Contributing to the Inability of Natural Killer Cells to Kill Epstein-Barr Virus–Infected B Cells in X-Linked Lymphoproliferative Disease
Authors: Cristina Bottino, Michela Falco, Silvia Parolini, Emanuela Marcenaro, Raffaella Augugliaro, Simona Sivori, Elena Landi, Roberto Biassoni, Luigi D. Notarangelo, Lorenzo Moretta, Alessandro Moretta
Journal: The Journal of Experimental Medicine (2001)

In humans, natural killer (NK) cell function is regulated by a series of receptors and coreceptors with either triggering or inhibitory activity. Here we describe a novel 60-kD glycoprotein, termed NTB-A, that is expressed by all human NK, T, and B lymphocytes. Monoclonal antibody (mAb)-mediated cross-linking of NTB-A results in the induction of NK-mediated cytotoxicity. Similar to 2B4 (CD244) functioning as a coreceptor in the NK cell activation, NTB-A also triggers cytolytic activity only in NK cells expressing high surface densities of natural cytotoxicity receptors. This suggests that also NTB-A may function as a coreceptor in the process of NK cell activation. Molecular cloning of the cDNA coding for NTB-A molecule revealed a novel member of the immunoglobulin superfamily belonging to the CD2 subfamily. NTB-A is characterized, in its extracellular portion, by a distal V-type and a proximal C2-type domain and by a cytoplasmic portion containing three tyrosine-based motifs. NTB-A undergoes tyrosine phosphorylation and associates with the Src homology 2 domain–containing protein (SH2D1A) as well as with SH2 domain–containing phosphatases (SHPs). Importantly, analysis of NK cells derived from patients with X-linked lymphoproliferative disease (XLP) showed that the lack of SH2D1A protein profoundly affects the function not only of 2B4 but also of NTB-A. Thus, in XLP-NK cells, NTB-A mediates inhibitory rather than activating signals. These inhibitory signals are induced by the interaction of NTB-A with still undefined ligands expressed on Epstein-Barr virus (EBV)-infected target cells. Moreover, mAb-mediated masking of NTB-A can partially revert this inhibitory effect while a maximal recovery of target cell lysis can be obtained when both 2B4 and NTB-A are simultaneously masked. Thus, the altered function of NTB-A appears to play an important role in the inability of XLP-NK cells to kill EBV-infected target cells.
Prognostication in comatose survivors of cardiac arrest: An advisory statement from the European Resuscitation Council and the European Society of Intensive Care Medicine
Authors: Claudio Sandroni, Alain Cariou, Fabio Cavallaro, Tobias Cronberg, Hans Friberg, Cornelia Hoedemaekers, Janneke Horn, Jerry P. Nolan, Andrea O. Rossetti, Jasmeet Soar
Journal: Intensive Care Medicine (2014)

To review and update the evidence on predictors of poor outcome (death, persistent vegetative state or severe neurological disability) in adult comatose survivors of cardiac arrest, either treated or not treated with controlled temperature, to identify knowledge gaps and to suggest a reliable prognostication strategy.GRADE-based systematic review followed by expert consensus achieved using Web-based Delphi methodology, conference calls and face-to-face meetings. Predictors based on clinical examination, electrophysiology, biomarkers and imaging were included.Evidence from a total of 73 studies was reviewed. The quality of evidence was low or very low for almost all studies. In patients who are comatose with absent or extensor motor response at ≥ 72 h from arrest, either treated or not treated with controlled temperature, bilateral absence of either pupillary and corneal reflexes or N20 wave of short-latency somatosensory evoked potentials were identified as the most robust predictors. Early status myoclonus, elevated values of neuron-specific enolase at 48-72 h from arrest, unreactive malignant EEG patterns after rewarming, and presence of diffuse signs of postanoxic injury on either computed tomography or magnetic resonance imaging were identified as useful but less robust predictors. Prolonged observation and repeated assessments should be considered when results of initial assessment are inconclusive. Although no specific combination of predictors is sufficiently supported by available evidence, a multimodal prognostication approach is recommended in all patients.
Increased Short-Term Variability of Repolarization Predicts <i>d</i> -Sotalol–Induced Torsades de Pointes in Dogs
Authors: Morten B. Thomsen, S. Cora Verduyn, Milan Stengl, Jet D.M. Beekman, Geert de Pater, Jurren van Opstal, Paul G.A. Volders, Marc A. Vos
Journal: Circulation (2004)

Identification of patients at risk for drug-induced torsades de pointes arrhythmia (TdP) is difficult. Increased temporal lability of repolarization has been suggested as being valuable to predict proarrhythmia. The predictive value of different repolarization parameters, including beat-to-beat variability of repolarization (BVR), was compared in this serial investigation in dogs with chronic AV block.In anesthetized dogs with electrically remodeled hearts, the dose-dependent difference in drug-induced TdP (d-sotalol, 2 and 4 mg/kg IV over 5 minutes, 25% and 75% TdP, respectively) could not be accounted for by prolongation of QT(c) (410+/-37 to 475+/-60 versus 415+/-47 to 484+/-52 ms, respectively). BVR was quantified by Poincare plots at baseline and immediately before onset of d-sotalol-induced extrasystolic activity. TdP occurrence was associated with an increase in short-term variability (STV) of the left ventricular monophasic action potential duration (3.5+/-1.5 to 5.5+/-1.6 versus 3.0+/-0.7 to 8.6+/-3.8 ms, respectively), which was reversible when TdP was abolished by I(K,ATP) activation. The absence of TdP despite QT(c) prolongation after chronic amiodarone treatment could also be explained by an unchanged STV. In experiments with isolated ventricular myocytes, STV increased after I(Kr) block and was highest in cells that subsequently showed early afterdepolarizations.Proarrhythmia is not related to differences in prolongation of repolarization but corresponds to BVR, here quantified as STV of the left ventricle. STV could be a new parameter to predict drug-induced TdP in patients.
A mutated beta-catenin gene encodes a melanoma-specific antigen recognized by tumor infiltrating lymphocytes.
Authors: P F Robbins, M El-Gamil, Y F Li, Y Kawakami, D Loftus, E Appella, S A Rosenberg
Journal: The Journal of Experimental Medicine (1996)

A number of antigens recognized by tumor-reactive T cells have recently been identified. The antigens identified in mouse model systems appear, with one exception, to represent the products of mutated genes. In contrast, most of the antigens recognized by human tumor-reactive T cells reported to date appear to represent the products of non-mutated genes. Here we report the isolation of a cDNA clone encoding beta-catenin, which was shown to be recognized by the tumor-infiltrating lymphocyte (TIL) 1290, a HLA-A24 restricted melanoma-specific CTL line from patient 888. The cDNA clone, which was isolated from the autologous melanoma cDNA library, differed by a single base pair from the published beta-catenin sequence, resulting in a change from a serine to a phenylalanine residue at position 37. Normal tissues from this patient did not express the altered sequence, nor did 12 allogeneic melanomas, indicating that this represented a unique mutation in this patient's melanoma. A peptide corresponding to the sequence between amino acids 29 and 37 of the mutant gene product was identified as the T cell epitope recognized by TIL 1290. The observation that HLA-A24 binding peptides contain an aromatic or hydrophobic residue at position 9 suggested that the change at position 37 may have generated a peptide (SYLDSGIHF) which was capable of binding to HLA-A24, and a competitive binding assay confirmed this hypothesis. The beta-catenin protein has been shown previously to be involved in cell adhesion mediated through the cadherin family of cell surface adhesion molecules. The high frequency of mutations found in members of cellular adhesion complexes in a variety of cancers suggests that these molecules may play a role in development of the malignant phenotype.
Lost in Translation: A Fisherman's Tale
Authors: Michael J. Overman, Daniel E. Epner
Journal: Journal of Clinical Oncology (2011)

The Fisherman Mr. B was a 76-year-old Kuwaiti man with a history of rectal bleeding and progressive fatigue for several months. He had worked as a carpenter and welder his entire life and was an avid fisherman in his spare time. Blood work in Kuwait revealed severe anemia, and colonoscopy detected a large rectal mass, the biopsy of which confirmed adenocarcinoma. Staging computedtomography(CT)inKuwaitshoweda10 5—cm rectal mass that involved bladder and seminal vesicles (T4 primary). He received 3 units of RBCs and then traveled to the United States with his brother and son for evaluation and treatment. A repeat CT in our clinic confirmed locally advanced rectal cancer, and blood work demonstrated moderate anemia. He did not take any regular medications and had no significant past medical history. As I viewed the CT images of his extensive primary tumor, I realized that his treatment would be complex and potentially risky. In addition, obtaining informed consent for a complex, multimodality treatment would be involved, given that an Arabic interpreter would serve as intermediary.
Evidence for Two Components of Delayed Rectifier K <sup>+</sup> Current in Human Ventricular Myocytes
Authors: Gui-Rong Li, Jianlin Feng, Lixia Yue, Michel Carrier, Stanley Nattel
Journal: Circulation Research (1996)

Previous voltage-clamp studies have suggested that the delayed rectifier current (IK) is small or absent in the human ventricle and, when present, consists only of the rapid component (IKr); however, molecular studies suggest the presence of functionally important IK in the human heart, specific IKr blockers are known to delay ventricular repolarization and cause the long QT syndrome in humans, and we have shown that the expression of IK is strongly influenced by cell isolation techniques. The present experiments were designed to assess the expression of IK in myocytes obtained by arterial perfusion of right ventricular tissue from explanted human hearts. Of 35 cells from three hearts, 33 (94%) showed time-dependent currents typical of IK. The envelope-of-tails test was not satisfied under control conditions but became satisfied in the presence of the benzenesulfonamide E-4031 (5 micromol/L). E-4031 suppressed a portion of IK in 32 of 33 cells, with properties of the drug-sensitive and -resistant components consistent with previous descriptions of IKr and the slow component (IKs), respectively. Action potential duration to 95% repolarization at 1 Hz was prolonged by E-4031 from 336+/-16 (mean +/- SEM) to 421 +/- 19ms (n = 5, P < .01), indicating a functional role for IK. Indapamide, a diuretic agent previously shown to inhibit IKs selectively, suppressed E-4031-resistant current. The presence of a third type of delayed rectifier, the ultrarapid delayed rectifier current (IKur), was evaluated with the use of depolarizing prepulses and low concentrations (50 micromol/L) of 4-aminopyridine. Although these techniques revealed clear IKur in five of five human atrial cells, no corresponding component was observed in any of five human ventricular myocytes. We conclude that a functionally significant IK, with components corresponding to IKr and IKs, is present in human ventricular cells, whereas IKur appears to be absent. These findings are important for understanding the molecular, physiological, and pharmacological determinants of human ventricular repolarization and arrhythmias.
Triple therapy for idiopathic pulmonary fibrosis
Authors: Mark G Jones
Journal: Thorax (2012)

Triple therapy for idiopathic pulmonary fibrosisThis multicentre, randomised, double-blind placebo-controlled trial was designed to address the effectiveness of the antioxidant, N-Acetylcysteine (NAC), alone and in 'triple' therapy ( prednisolone, azathioprine and NAC) in idiopathic pulmonary fibrosis (IPF).Patients with IPF and mild to moderate lung function impairment (FVC≥50% and TLCO≥30%) were assigned to receive triple therapy, NAC alone or matched placebo for 60 weeks.Target recruitment was 130 patients per group, however, following a planned interim analysis (mean follow-up 32 weeks) the triple therapy arm (n=77) was halted.Compared with placebo (n=78), increased risks of death (8 vs 1), hospitalisation (23 vs 7), and serious adverse events (24 vs 8) were seen.The placebo and triple therapy groups had no significant differences in demographic and clinical characteristics.No clinical or physiological benefit was seen with triple therapy.This is the first trial to compare triple therapy with placebo, and provides evidence that as a treatment for IPF, triple therapy increases risks of death and hospitalisation.The reasons for this, and which components might be responsible, are uncertain.The shortened duration of this trial limits comparison of mortality rates with previous trials when assessing if an aberrant outcome has occurred.This trial illustrates the importance of conducting placebo-controlled randomised trials to guide clinical practice when prescribing unproven and potentially harmful therapies.The NAC-only, and placebo groups, continue to recruit.In a disease with such limited treatment options and unmet clinical needs, further evidence for a therapeutic role of NAC is sorely needed.
Decision analysis in the surgical treatment of colorectal cancer due to a mismatch repair gene defect
Authors: W H de Vos tot Nederveen Cappel
Journal: Gut (2003)

<b>Background:</b> In view of the high risk of developing a new primary colorectal carcinoma (CRC), subtotal colectomy rather than segmental resection or hemicolectomy is the preferred treatment in hereditary non-polyposis colorectal cancer (HNPCC) patients. Subtotal colectomy however implies a substantial decrease in quality of life. To date, colonoscopic surveillance has been shown to reduce CRC occurrence. <b>Aims:</b> To compare the potential health effects in terms of life expectancy (LE) for patients undergoing subtotal colectomy or hemicolectomy for CRC. <b>Methods:</b> A decision analysis (Markov) model was created. Information on the 10 year risk of CRC after subtotal colectomy (4%) and hemicolectomy (16%) and stages of CRCs detected within a two year surveillance interval (32% Dukes' A, 54% Dukes' B, and 14% Dukes' C) were derived from two cohort studies. Five year survival rates used for the different Dukes stages (A, B, and C) were 98%, 80%, and 60%, respectively. Remaining LE values were calculated for hypothetical cohorts with an age at CRC diagnosis of 27, 47, and 67 years, respectively. Remaining LE values were also calculated for patients with CRC of Dukes' stage A. <b>Results:</b> The overall LE gain of subtotal colectomy compared with hemicolectomy at ages 27, 47, and 67 was 2.3, 1, and 0.3 years, respectively. Specifically for Dukes' stage A, this would be 3.4, 1.5, and 0.4 years. <b>Conclusions:</b> Unless surveillance results improve, subtotal colectomy still seems the preferred treatment for CRC in HNPCC in view of the difference in LE. For older patients, hemicolectomy may be an option as there is no appreciable difference in LE.
Skeletal actin mRNA increases in the human heart during ontogenic development and is the major isoform of control and failing adult hearts.
Authors: K R Boheler, L Carrier, D de la Bastie, P D Allen, M Komajda, J J Mercadier, K Schwartz
Journal: Journal of Clinical Investigation (1991)

Expression of the two sarcomeric actins, alpha-skeletal and alpha-cardiac, is regulated in the rodent heart in response to developmental, hormonal, and hemodynamic stimuli. Little is known in man, except that both isogenes were found to be coexpressed in three adult ventricles. In this report, we investigated the isoactin mRNA composition in ventricles from 21 control patients (4 fetal, 5 juvenile, 12 adult) and from 15 patients undergoing cardiac transplantation (5 idiopathic dilated cardiomyopathies, 5 ischemic myopathies with myocardial infarcts, 5 diverse etiologies) by two different and complementary techniques: RNA dot blot analysis with specific cDNA probes, and primer extensions with an oligonucleotide common to alpha-cardiac and alpha-skeletal actins. In the case of dot blot analysis, quantification of each isoform was performed by using as standards RNA transcripts obtained from cloned human alpha-actin sequences, and the total amount of sarcomeric actin mRNA was evaluated as a function of total poly(A+)RNA. We found that both isogenes are always coexpressed, and that the isoactin pattern changes during development. In utero and in neonatal hearts, alpha-skeletal actin mRNA represents less than or equal to 20% of sarcomeric actins, it increases to 48 +/- 6% during the first decade after birth and becomes the predominant isoform of adult hearts (60.4 +/- 8.5%). The 15 adult failing hearts exhibited the same isoactin pattern as the control ones (62.84 +/- 11.06%), and there was no difference in expression between patients with dilated cardiomyopathy or ischemic heart disease. These observations demonstrate that cardiac development in man, in contrast to rodent heart, is characterized by an up-regulation of the skeletal actin gene, the expression of which does not change in hypertrophied and failing hearts, and suggest that the actin and myosin heavy chain families are independently regulated in human heart.
Health and health care in transitional Europe
Authors: Kristina Fister, Martin McKee
Journal: BMJ (2005)

In December 2004 we called for papers that would document the impact on population health and on health systems of the transition from communism in Europe and central Asia.w1 Over the past 18 months, a series of events has focused the eyes of the world on this region. May 2004 saw the historic enlargement of the European Union. In Georgia, Ukraine, and Kyrgyzstan, popular uprisings have led to the removal of autocratic regimes; in Uzbekistan, a similar uprising ended in tragedy. Yet, despite coming to the attention of the world's mass media, this vast region characterised by diversity and shared problems has generated surprisingly few publications on health and health care. We hope that this theme issue—most of it contributed by researchers and authors from the region—will fill some of these gaps and will further stimulate much needed monitoring, research, and debate.

One of the key themes in this week's BMJ theme issue is the rising prevalence of HIV/AIDS in some countries of the region. For example, one paper focuses on Ukraine, which has the highest prevalence of HIV infection in Europe (estimated at 1.4% of the population) but lacks any systematic approach to prevention, treatment, or care.1 The authors report how information on the scale and nature of the problem is patchy and is not well known within Ukraine. An accompanying commentary emphasises the need for urgent international action to prevent a potential catastrophe.w2

Non-communicable diseases continue to dominate the overall burden of disease in the region.2 Yet some countries have seen marked reductions in mortality,3 and, although precise explanations for this remain a matter for discussion,w3 it is clear that much can be done to tackle the high toll from cardiovascular disease. As Marquez and Suhrcke note, however, continuing improvement will depend on much more evidence and better use of existing evidence4,5 to inform policy, as well as on the creation of systems to collect data regularly on risk factors for chronic disease.