tbuckley/cabot-search huggingface dataset:
Deep Molecular Response Is Reached by the Majority of Patients Treated With Imatinib, Predicts Survival, and Is Achieved More Quickly by Optimized High-Dose Imatinib: Results From the Randomized CML-Study IV
Authors: Rüdiger Hehlmann, Martin C. Müller, Michael Lauseker, Benjamin Hanfstein, Alice Fabarius, Annette Schreiber, Ulrike Proetel, Nadine Pletsch, Markus Pfirrmann, Claudia Haferlach, Susanne Schnittger, Hermann Einsele, Jolanta Dengler, Christiane Falge, Lothar Kanz, Andreas Neubauer, Michael Kneba, Frank Stegelmann, Michael Pfreundschuh, Cornelius F. Waller, Karsten Spiekermann, Gabriela M. Baerlocher, Gerhard Ehninger, Dominik Heim, Hermann Heimpel, Christoph Nerl, Stefan W. Krause, Dieter K. Hossfeld, Hans-Jochem Kolb, Joerg Hasford, Susanne Saußele, Andreas Hochhaus
Journal: Journal of Clinical Oncology (2013)

Deep molecular response (MR(4.5)) defines a subgroup of patients with chronic myeloid leukemia (CML) who may stay in unmaintained remission after treatment discontinuation. It is unclear how many patients achieve MR(4.5) under different treatment modalities and whether MR(4.5) predicts survival.Patients from the randomized CML-Study IV were analyzed for confirmed MR(4.5) which was defined as ≥ 4.5 log reduction of BCR-ABL on the international scale (IS) and determined by reverse transcriptase polymerase chain reaction in two consecutive analyses. Landmark analyses were performed to assess the impact of MR(4.5) on survival.Of 1,551 randomly assigned patients, 1,524 were assessable. After a median observation time of 67.5 months, 5-year overall survival (OS) was 90%, 5-year progression-free-survival was 87.5%, and 8-year OS was 86%. The cumulative incidence of MR(4.5) after 9 years was 70% (median, 4.9 years); confirmed MR(4.5) was 54%. MR(4.5) was reached more quickly with optimized high-dose imatinib than with imatinib 400 mg/day (P = .016). Independent of treatment approach, confirmed MR(4.5) at 4 years predicted significantly higher survival probabilities than 0.1% to 1% IS, which corresponds to complete cytogenetic remission (8-year OS, 92% v 83%; P = .047). High-dose imatinib and early major molecular remission predicted MR(4.5). No patient with confirmed MR(4.5) has experienced progression.MR(4.5) is a new molecular predictor of long-term outcome, is reached by a majority of patients treated with imatinib, and is achieved more quickly with optimized high-dose imatinib, which may provide an improved therapeutic basis for treatment discontinuation in CML.
The ACE gene polymorphism: the good, the bad and the ugly
Authors: Y Pinto
Journal: Cardiovascular Research (1999)

See article by Perticone et al. ([3], pages 192–199) in this issue. 

After its first entry into the scientific stage [1] the deletion polymorphism of the Angiotensin Converting Enzyme presented cardiovascular researchers with a grateful opportunity to explore genetic mechanisms in cardiovascular disease. However, after a Good start, conflicting results gave the genotype a Bad reputation, and the stage now looks rather Ugly. After having discovered how promiscuously ACE behaves as an enzyme, it became apparent that the genotype was not much more faithful, being associated with an enormous variety of cardiovascular disorders, ranging from an association with myocardial infarction, vascular changes, even to issues like the ability to increase one’s physical performance [2].

In this issue of Cardiovascular Research Perticone et al. [3] report in a carefully executed study an association between the Angiotensin Converting Enzyme (ACE) deletion type gene and the prevalence of left ventricular hypertrophy in a population of untreated italian hypertensives. One of the most striking findings was that the deletion type allele of ACE was related to a more eccentric type of hypertrophy. This data further extends earlier observations suggesting a relation between the ACE genotype and left ventricular hypertrophy [4] and the relation between the ACE genotype and the … 

* Corresponding author. Tel.: +31-50-363-2810; fax: +31-50-363-2812.
Dendritic Cells Cross-Present Latency Gene Products from Epstein-Barr Virus–Transformed B Cells and Expand Tumor-Reactive Cd8+ Killer T Cells
Authors: Marion Subklewe, Casper Paludan, Ming L. Tsang, Karsten Mahnke, Ralph M. Steinman, Christian Münz
Journal: The Journal of Experimental Medicine (2001)

Dendritic cells (DCs) are not targets for infection by the transforming Epstein-Barr virus (EBV). To test if the adjuvant role of DCs could be harnessed against EBV latency genes by cross-presentation, DCs were allowed to process either autologous or human histocompatibility leukocyte antigen (HLA)-mismatched, transformed, B lymphocyte cell lines (LCLs) that had been subject to apoptotic or necrotic cell death. After phagocytosis of small numbers of either type of dead LCL, which lacked direct immune-stimulatory capacity, DCs could expand CD8+ T cells capable of killing LCLs that were HLA matched to the DCs. Necrotic EBV-transformed, major histocompatibility complex (MHC) class I–negative LCLs, when presented by DCs, also could elicit responses to MHC class II–negative, EBV-transformed targets that were MHC class I matched to the DCs, confirming efficient cross-presentation of LCL antigens via MHC class I on the DC. Part of this EBV-specific CD8+ T cell response, in both lytic and interferon γ secretion assays, was specific for the EBV nuclear antigen (EBNA)3A and latent membrane protein (LMP)2 latency antigens that are known to be expressed at low levels in transformed cells. The induced CD8+ T cells recognized targets at low doses, 1–10 nM, of peptide. Therefore, the capacity of DCs to cross-present antigens from dead cells extends to the expansion of high affinity T cells specific for viral latency antigens involved in cell transformation.
Myelin Basic Protein–specific T Helper 2 (Th2) Cells Cause Experimental Autoimmune Encephalomyelitis in Immunodeficient Hosts Rather than Protect Them from the Disease
Authors: Juan J. Lafaille, Fabienne Van de Keere, Albert L. Hsu, Jody L. Baron, Werner Haas, Cedric S. Raine, Susumu Tonegawa
Journal: The Journal of Experimental Medicine (1997)

Chronic inflammatory autoimmune diseases such as multiple sclerosis, diabetes, and rheumatoid arthritis are caused by CD4+ Th1 cells. Because Th2 cells antagonize Th1 cell functions in several ways, it is believed that immune deviation towards Th2 can prevent or cure autoimmune diseases. Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease used as a model for multiple sclerosis. Using an adoptive transfer system we assessed the role of Th1 and Th2 cells in EAE. In vitro generated Th1 and Th2 cells from myelin basic protein (MBP)-specific TCR transgenic mice were transferred into normal and immunodeficient mice. Th1 cells caused EAE in all recipients after a brief preclinical phase. Surprisingly, Th2 cells also caused EAE in RAG-1 KO mice and in αβ T cell–deficient mice, albeit after a longer preclinical phase. Normal or γδ T cell–deficient mice were resistant to EAE induced by Th2 cells. The histopathological features of this disease resembled those of an allergic process. In addition, disease induction by Th1 cells was not altered by coadmininstration of Th2 cells in any of the recipients. These findings indicate that MBP-specific Th2 cells have the potential to induce EAE and that the disease induced by previously activated Th1 cells cannot be prevented by normal lymphocytes nor by previously activated Th2 cells.
Reversal of Digoxin Toxicity with Specific Antibodies
Authors: Donald H. Schmidt, Vincent P. Butler
Journal: Journal of Clinical Investigation (1971)

To determine whether digoxin-specific antibodies can reverse established digoxin toxicity in the dog, digoxin intoxication was produced by the intramuscular administration of digoxin, 0.09 mg/kg, on each of 3 consecutive days. All animals developed toxic arrhythmias (atrioventricular block, ventricular premature contractions and/or ventricular tachycardia). In control animals not receiving antidigoxin antibodies, the arrhythmias persisted throughout a 6 hr study period. Seven of the nine control dogs were dead within 24 hr and one moribund animal was sacrificed at that time; the last animal died within 48 hr.In contrast, in six of eight dogs given digoxin-specific antibodies in canine plasma and/or rabbit serum, the arrhythmias reverted to a sinus mechanism within 30-90 min after the start of the infusion. At the end of a 6 hr period of study, these six dogs were in normal sinus rhythm and all eight were alive and in normal sinus rhythm at the end of 72 hr. This study provides evidence that digoxin-specific antibodies can reverse severe established digoxin toxicity in the dog.
Psoriatic onychopachydermoperiostitis: improvement with etanercept
Authors: M. Dans, C. Hivnor, A.S. Van Voorhees
Journal: British Journal of Dermatology (2005)

Journal Article Psoriatic onychopachydermoperiostitis: improvement with etanercept Get access M. Dans, M. Dans Department of Dermatology, University of Pennsylvania School of Medicine, 2 Maloney Building, 3600 Spruce Street, Philadelphia, PA 19104, U.S.A Search for other works by this author on: Oxford Academic Google Scholar C. Hivnor, C. Hivnor Department of Dermatology, University of Pennsylvania School of Medicine, 2 Maloney Building, 3600 Spruce Street, Philadelphia, PA 19104, U.S.A Search for other works by this author on: Oxford Academic Google Scholar A.S. Van Voorhees A.S. Van Voorhees Department of Dermatology, University of Pennsylvania School of Medicine, 2 Maloney Building, 3600 Spruce Street, Philadelphia, PA 19104, U.S.A A.S. van Voorhees. E‐mail: vanvoora@uphs.upenn.edu Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 153, Issue 4, 1 October 2005, Pages 858–859, https://doi.org/10.1111/j.1365-2133.2005.06867.x Published: 01 October 2005
Translational control of interleukin 2 messenger RNA as a molecular mechanism of T cell anergy.
Authors: J A Garcia-Sanz, D Lenig
Journal: The Journal of Experimental Medicine (1996)

T cell stimulation by triggering through the T cell receptor (TCR) in the absence of costimulatory signals or by calcium ionophore induces unresponsiveness in T cells to further stimulation, a phenomenon known as anergy. In freshly isolated T cells, calcium ionophore induces expression of interleukin (IL)-2 messenger (mRNA), but this mRNA is not translated and not loaded with ribosomes. In addition, while plate-bound anti-CD3 stimulation of resting T cells leads to IL-2 mRNA expression and IL-2 secretion, in cells pretreated with calcium ionophore before anti-CD3 stimulation, the IL-2 mRNA remains polysome unloaded and no IL-2 is produced. These observations show that IL-2 expression is controlled at the translational level, by differential ribosome loading. Furthermore, our data suggest that translational control of IL-2 mRNA may be a molecular mechanism by which anergy is attained.
In vitro of adenosine on lymphocytes and erythrocytes from horses with combined immunodeficiency.
Authors: N S Magnuson, L E Perryman
Journal: Journal of Clinical Investigation (1979)

The effect of adenosine on the mitogenic response of peripheral blood lymphocytes (PBL) and on the nucleotide pools of erythrocytes from normal horses, horses heterozygous for the combined immunodeficiency (CID) trait (carriers), and foals with CID was studied. When PBL from normal, carrier, and CID horses were stimulated by phytohemagglutinin (PHA), concanavalin A, or pokeweed mitogen, [3H]thymidine uptake was inhibited by adenosine (0.1 microM) to 1.0 mM) in a dose-dependent manner. Adenosine (100 microM) mediated inhibition of [3H]thymidine uptake was prevented in both normal and carrier horse PBL by incubation with uridine. Uridine had no sparing effect on PBL from horses with CID. Differences were detected between human and horse PBL in response to adenosine and erythro-9(2-hydroxy-3-nonyl) adenine (EHNA), a competitive inhibitor of adenosine deaminase. In the first assay, mitogen-stimulated PBL from horses were more sensitive to adenosine. In the second assay, adenosine was added to PBL cultures at various times after PHA addition. Adenosine inhibited mitogenesis in horse PBL if added within the first 24 h. In human PBL cultures, adenosine inhibited mitogenesis only if added within the first 4 h. The third assay measured capacity of PHA-stimulated human and horse lymphocytes to escape inhibition by adenosine or EHNA. At the end of a 72-h culture period, horse PBL were still inhibited of mitogenesis in both human and horse PBL. With prolonged incubation (72 h), synergistic inhibition was detected only in horse PB. With high-pressure liquid chromatography, nucleotide levels in erythrocytes of normal, carrier, and CID horses were found to be similar. Incubation with adenosine produced a 1.5- to 2-fold increase in total adenine nucleotide pools in erythrocytes from all horses. However, these increases were accompanied by alterations in the relative amounts of the nucleotide components. This was seen as a significant decrease in the ATP:(AMP plus ADP plus ATP) ratio and energy charge in erythrocytes from normal horses. In contrast, the ATP:(AMP plus ADP plus ATP) ratio decreased only slightly in erythrocytes from CID horses, whereas no change in the energy charge was detected. The data from these studies indicate a difference in adenosine metabolism exists between human and horse lymphoyctes, and an abnormality may exist in purine metabolism or in an interconnecting pathway in horses with CID.
IgG monoclonal gammopathy in four patients with polymyalgia rheumatica.
Authors: D Ilfeld, J Barzilay, D Vana, M Ben-Bassat, H Joshua, I Pick
Journal: Annals of the Rheumatic Diseases (1985)

CorrespondenceIgG monoclonal gammopathy in four patients with polymyalgia rheumatica mouse artery y 1:10 y 1:10 K 1:40Sections of mouse femoral artery were incubated with sera from four patients with IgG BMG and PMR (with or without GCA) and sera from four controls with IgG BMG, one control with GCA, and one control with PMR, washed, incubated with fluorescein isothiocyanate-labelled goat antihuman y. c, a, K, or A antisera, and examined by fluorescent microscopy.*TA=temporal artery.tND=not done.
The emerging problem of biological treatment in migrant and travelling populations: it is time to extend guidelines for the screening of infectious diseases
Authors: F Bartalesi, A Bartoloni, Z Bisoffi, M Spinicci, F Giménez Sánchez, J Muñoz, P Richi, G Minisola, S Muñoz-Fernandez, M Matucci-Cerinic
Journal: Annals of the Rheumatic Diseases (2013)

The use of biological agents in the treatment of rheumatic diseases has been widely associated with an increased risk of reactivation of several latent infections. National and international guidelines recommend screening for infectious diseases before starting these drugs. In Western countries screening is limited to latent tuberculosis infection, HIV and viral hepatitis. However, the increasing globalisation and the remarkable number of migrating and travelling people worldwide make this approach no longer adequate. The Italian and Spanish Societies of Rheumatology and Tropical Medicine wish to issue a warning about the need to improve awareness of doctors about the risk of reactivation of infectious tropical diseases in migrant or travelling patients who undergo biological therapy. Thus, the Italian and Spanish Societies are now planning to issue specific recommendations, based on a multidisciplinary contribution and a systematic review of the literature, for screening and follow-up of active and latent chronic infections in candidate patients for biological agents, taking into account the patient's area of origin and risk of infectious diseases.
Angiotensin II- and Salt-Induced Kidney Injury through Rac1-Mediated Mineralocorticoid Receptor Activation
Authors: Wakako Kawarazaki, Miki Nagase, Shigetaka Yoshida, Maki Takeuchi, Kenichi Ishizawa, Nobuhiro Ayuzawa, Kohei Ueda, Toshiro Fujita
Journal: Journal of the American Society of Nephrology (2012)

Experiments with hyperaldosteronemic animals suggest that, despite lowering plasma aldosterone, salt worsens renal injury by paradoxical activation of the mineralocorticoid receptor (MR). Salt and aldosterone synergistically contribute to renal impairment through Rac1-mediated activation of the MR, but whether angiotensin II also promotes renal injury through this mechanism is unknown. Here, we placed angiotensin II-overproducing double transgenic Tsukuba hypertensive mice on a low- or high-salt intake for 6 weeks and treated some animals with adrenalectomy, the MR antagonist eplerenone, the Rac inhibitor EHT1864, or hydralazine. High-salt intake, but not low-salt intake, led to hypertension and prominent kidney injury. Adrenalectomy prevented angiotensin II/salt-induced nephropathy in mice receiving high-salt intake, which was recapitulated by aldosterone supplementation, suggesting the involvement of aldosterone/MR signaling. Plasma aldosterone levels, however, were lower in high- than low-salt conditions. Instead, angiotensin II/salt-evoked MR activation associated with Rac1 activation and was not dependent on plasma aldosterone level. Both EHT1864 and eplerenone repressed the augmented MR signaling and mitigated kidney injury with partial but significant reduction in BP with high-salt intake. Hydralazine similarly reduced BP, but it neither suppressed the Rac1-MR pathway nor ameliorated the nephropathy. Taken together, these results show that angiotensin II and salt accelerate kidney injury through Rac1-mediated MR activation. Rac inhibition may be a promising strategy for the treatment of CKD.
Glucagon-like peptide-1 as a treatment for chemotherapy-induced mucositis
Authors: Hannelouise Kissow, Bolette Hartmann, Jens Juul Holst, Steen Seier Poulsen
Journal: Gut (2012)

Glucagon-like peptide-2 (GLP-2) has been suggested for the treatment of mucositis, but the peptide has also been shown to accentuate colonic dysplasia in carcinogen-treated mice. Recently, an effect on intestinal growth was discovered for glucagon-like peptide-1 (GLP-1), OBJECTIVE: To determine whether endogenous GLP-1 contributes to the healing processes and if exogenous GLP-1 has a potential role in treating mucositis.Mice were injected with 5-fluorouracil (5-FU) or saline to induce mucositis and were then treated with GLP-1, GLP-2, GLP-2 (3-33), exendin (9-39) or vehicle. The mice were sacrificed 48 or 96 h after the 5-FU injections. The end points were intestinal weight, villus height, proliferation and histological scoring of mucositis severity. Rats were injected with 5-FU or saline, and after 48 h, blood was drawn and analysed for GLP-1 and GLP-2 concentration.GLP-1 and GLP-2 significantly prevented the loss of mucosal mass and villus height and significantly decreased the mucositis severity score in the duodenum and jejunum 48 h after chemotherapy. The effect was equivalent. Exendin (9-39) reduced the intestinal weight 96 h after chemotherapy. The GLP-1 levels in blood were increased more than 10-fold, and GLP-2 levels were increased sevenfold.GLP-1 and GLP-2 were secreted after intestinal injury, and recovery was delayed after treatment with exendin (9-39), indicating an important role for the peptides in the protection of the intestine from injury. GLP-1 treatment ameliorated mucositis, which suggests that mucositis and other acute intestinal disorders might benefit from treatment with GLP-1 analogues.
A multicenter phase II study of pazopanib in patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib
Authors: K.N. Ganjoo, V.M. Villalobos, A. Kamaya, G.A. Fisher, J.E. Butrynski, J.A. Morgan, A.J. Wagner, D. D'Adamo, A. McMillan, G.D. Demetri, S. George
Journal: Annals of Oncology (2013)
Scintigraphic documentation of an improvement in hepatobiliary excretory function after treatment with ursodeoxycholic acid in patients with cystic fibrosis and associated liver disease
Authors: Carla Colombo, Maria Rita Castellani, William F. Balistreri, Ettore Seregni, Maria Luisa Assaisso, Annamaria Giunta
Journal: Hepatology (1992)

We have previously documented that ursodeoxycholic acid exerts a beneficial effect on liver function and bile acid metabolism in patients with cystic fibrosis. We hypothesized that the mechanism of action may be related in part to the choleretic properties of the administered bile acid. We therefore compared hepatobiliary scintigraphic images obtained before and 1 yr after initiation of ursodeoxycholic acid therapy to document an improvement in bile flow in 13 patients with cystic fibrosis and hepatobiliary involvement. Before therapy, hepatobiliary scintigraphy documented biliary stasis with retention of the isotope in intrahepatic and extrahepatic bile ducts in nine patients; during therapy, duct dilatation decreased substantially in eight patients, with decreased intrahepatic retention and more rapid biliary outflow of the tracer. The time of appearance of isotope in the intestine decreased (from a mean of 36.9 ± 17.8 min to 18.8 ± 9.0 min; p &lt; 0.01) in all patients in whom it had been abnormal, and the half–time of hepatic washout decreased from a mean of 35 ± 20.7 min to 26 ± 15.6 min (p &lt; 0.05). During ursodeoxycholic acid administration enrichment of bile was achieved, with the mean ursodeoxycholic acid percent composition increasing from 5.8% ± 2.9% to 35.7% ± 8.5%. Ursodeoxycholic acid became the predominant bile acid in serum. Liver function improved in all 10 of the patients with abnormal values at baseline. We conclude that hepatobiliary scintigraphy is of value in monitoring the therapeutic responses of cystic fibrosis patients with liver disease to ursodeoxycholic acid therapy. These scintigraphic changes observed in our patients after treatment with ursodeoxycholic acid confirm the therapeutic effect of this bile acid in cystic fibrosis patients with associated liver disease. The effect may be mediated through an improvement in canalicular excretory function and biliary drainage. (Hepatology 1992;15:677-684).
Life after Death: A Practical Approach to Grief and Bereavement
Authors: David Casarett, Jean S. Kutner, Janet Abrahm
Journal: Annals of Internal Medicine (2001)

This consensus paper describes the essential skills that clinicians need to help persons who are experiencing grief after the death of a loved one. Four aspects of the grieving process are reviewed: anticipatory grief, acute grief, normal grief reactions, and complicated grief. Techniques for assessment and recommendations about interventions and indications for referral are provided for each aspect.