tbuckley/cabot-search huggingface dataset:
Clinical activity of a cytotoxic fusion protein in the treatment of cutaneous T-cell lymphoma.
Authors: P Hesketh, P Caguioa, H Koh, H Dewey, A Facada, R McCaffrey, K Parker, P Nylen, T Woodworth
Journal: Journal of Clinical Oncology (1993)

PURPOSE A phase I trial in patients with refractory hematologic malignancies was performed at our institution to test the clinical relevance of the selective cytotoxic activity of the interleukin-2 (IL-2)-diphtheria toxin fusion protein, DAB486IL-2. A subset of five patients from this trial, all with cutaneous T-cell lymphomas (CTCL), forms the basis of this report. PATIENTS AND METHODS Two treatment schedules were used. One patient received DAB486IL-2 at a dose of 0.075 mg/kg/d intravenous (i.v.) bolus over 15 minutes daily for 5 consecutive days. The other four patients received DAB486IL-2 at a dose of 0.1 mg/kg as an i.v. infusion over 180 minutes weekly for 5 consecutive weeks. RESULTS Three of the five CTCL patients achieved significant tumor responses. One patient attained a complete clinical and pathologic response (CR), which has been sustained without any interval treatment for 33+ months. Two other patients achieved partial responses (PRs) of 17+ and 4 months' duration, respectively. Treatment was well tolerated. The most common adverse effect was a transient increase in hepatic transaminases experienced by all five patients. CONCLUSION The growth factor-cytotoxin fusion protein DAB486IL-2 demonstrated significant clinical activity with acceptable toxicity in a group of heavily pretreated patients with CTCL.
Autoantibodies of patients with coeliac disease are insufficient to block tissue transglutaminase activity
Authors: W Dieterich
Journal: Gut (2003)

<b>Background and aims:</b> Coeliac disease (CD) is characterised by the presence of autoantibodies against tissue transglutaminase (tTG), the endomysial autoantigen. This study was performed to determine the effect of purified autoantibodies on the enzymatic activity of tTG. <b>Methods:</b> Total IgA and IgG class antibodies and purified anti-tTG autoantibodies were isolated from sera of untreated patients with CD and controls. The inhibitory capacity of the antibodies on tTG activity was checked by a fluorometric assay based on the incorporation of monodansyl cadaverine into casein and by tTG-catalysed cross linking of biotinylated cadaverine to gliadin. <b>Results:</b> The enriched IgA and IgG fractions of five patients with CD and three controls resulted in no significantly different inhibition of enzymatic activity. In contrast, the use of affinity purified anti-tTG autoantibodies of 12 patients with CD led to a dose dependent reduction of tTG activity, compared to control immunoglobulins (n=6). However, the remaining activity was sufficient for cross linking of cadaverine into gliadin, and enzymatic tTG activity was only blocked completely by high concentrations of a monoclonal antibody, which is directed to the active centre of tTG. <b>Conclusions:</b> Despite a partial inhibitory effect of isolated anti-tTG autoantibodies from patients with CD, residual enzymatic activity remains sufficiently high to cast doubt on their in vivo relevance.
Guideline-based Consultation To Prevent Anticoagulant-related Bleeding
Authors: C. Seth Landefeld, Philip A. Anderson
Journal: Annals of Internal Medicine (1992)

To test the efficacy of consultation designed to prevent anticoagulant-related bleeding.Randomized, controlled trial.A large teaching hospital.A total of 101 patients at increased (greater than 15%) risk for major, in-hospital bleeding while starting long-term anticoagulant therapy who were identified using a validated prediction rule.Fifty-five patients received usual care under the direction of the attending physician who had initiated anticoagulant therapy. Forty-six patients received guideline-based consultation in addition to usual care. Guideline-based consultation included individualized review of the risks and benefits of anticoagulant therapy and, on the basis of current practice guidelines, recommendations for daily management.The main outcome was in-hospital bleeding, which was classified using a reliable, explicit index.Major or minor bleeding occurred in 17 of 55 patients (31%) receiving usual care alone, compared with 6 of 46 patients (13%) receiving consultation in addition to usual care (P = 0.03). The protective efficacy of consultation was 58% (95% CI, 3% to 82%). Consultation was associated with similar reductions in the frequencies of major bleeding (from 13% to 4%) and minor bleeding (from 18% to 9%). Consultative recommendations had an 84% compliance rate and directly affected anticoagulant management: In the consult group, nonsteroidal anti-inflammatory agents were stopped in six patients (13%), and therapeutic ranges were achieved more often for activated partial thromboplastin times (52% compared with 45% in the usual care group, P = 0.08) and for prothrombin times (47% compared with 27% in the usual care group, P less than 0.001). Nearly all housestaff and attending physicians (91%) for patients receiving consultation also reported that consultation improved housestaff learning. The consult group had a somewhat lower rate of thromboembolism in the 90 days after discharge (5% compared with 17%, P = 0.06). Death rates and mean lengths of stay were similar in the two groups.Guideline-based consultation was associated with reduction in the frequency of anticoagulant-related bleeding in patients at increased risk for major in-hospital bleeding.
Allogeneic Cardiospheres Safely Boost Cardiac Function and Attenuate Adverse Remodeling After Myocardial Infarction in Immunologically Mismatched Rat Strains
Authors: Eleni Tseliou, Sara Pollan, Konstantinos Malliaras, John Terrovitis, Baiming Sun, Giselle Galang, Linda Marbán, Daniel Luthringer, Eduardo Marbán
Journal: Journal of the American College of Cardiology (2013)
I-A-restricted T cell antigen recognition. Analysis of the roles of A alpha and A beta using DNA-mediated gene transfer.
Authors: R I Lechler, F Ronchese, N S Braunstein, R N Germain
Journal: The Journal of Experimental Medicine (1986)

The contributions of A alpha and A beta chains, and of subregions of A beta, to Ia-restricted recognition of antigen by Th lymphocytes were analyzed using a panel of L cells transfected with various pairs of A alpha b,d, or k genes and recombinant or wild-type A beta b,d, or k genes. The A beta genes included all possible exchanges of the whole NH2-terminal (beta 1) domain or halves of the beta 1 domain among these three allelic A beta genes. The Ia+ L cells derived from such transfections were used as antigen-presenting cells with a 21 member panel of responding Ia-restricted T hybridoma cells of differing nominal antigen specificity and Ia-restriction. Special care was taken to account for quantitative variation in levels of Ia expression throughout the experiments. The results of this analysis reveal that (a) only 2 of the 21 Th cells recognized Ia molecules involving either a nonparental A alpha or a nonparental A beta chain, and in both cases the degeneracy extended to only one of the two other alleles tested. This suggests that allele specific contributions from both A alpha and A beta chains are important in restricted recognition for most, if not all I-A-restricted Th cells. (b) In no case did substitution of the A beta 2 domain from either of the alternative haplotypes lead to any functionally detectable effects, demonstrating that polymorphisms in the A beta 1 domain can entirely account for the restriction imposed on Th cell responses by the entire A beta chain. (c) For 90% of the cells tested, replacement of the NH2-terminal portion of the beta 1 domain with an allogeneic segment led to Ia molecules unable to elicit Th responses. Furthermore, of all the cells permissive of the substitution of one or other half of the beta 1 domain, only two permitted the substitution of sequence from both alternative haplotypes. Taken together, these data strongly suggest that antigen recognition by most, if not all, I-A-restricted Th cells involves contributions from both halves of the A beta 1 domain. These data suggest that the role of I-A molecules in restricted Th cell recognition of antigen depends on conformational determinants unique to a particular combination of polymorphic alpha and beta chains, and that multiple such sites exist on a single Ia molecule.(ABSTRACT TRUNCATED AT 400 WORDS)
Functional Magnetic Resonance Imaging of Impaired Sensory Prediction in Schizophrenia
Authors: Sukhwinder S. Shergill, Thomas P. White, Daniel W. Joyce, Paul M. Bays, Daniel M. Wolpert, Chris D. Frith
Journal: JAMA Psychiatry (2013)

Forward models predict the sensory consequences of planned actions and permit discrimination of self- and non-self-elicited sensation; their impairment in schizophrenia is implied by an abnormality in behavioral force-matching and the flawed agency judgments characteristic of positive symptoms, including auditory hallucinations and delusions of control.To assess attenuation of sensory processing by self-action in individuals with schizophrenia and its relation to current symptom severity.Functional magnetic resonance imaging data were acquired while medicated individuals with schizophrenia (n = 19) and matched controls (n = 19) performed a factorially designed sensorimotor task in which the occurrence and relative timing of action and sensation were manipulated. The study took place at the neuroimaging research unit at the Institute of Cognitive Neuroscience, University College London, and the Maudsley Hospital.In controls, a region of secondary somatosensory cortex exhibited attenuated activation when sensation and action were synchronous compared with when the former occurred after an unexpected delay or alone. By contrast, reduced attenuation was observed in the schizophrenia group, suggesting that these individuals were unable to predict the sensory consequences of their own actions. Furthermore, failure to attenuate secondary somatosensory cortex processing was predicted by current hallucinatory severity.Although comparably reduced attenuation has been reported in the verbal domain, this work implies that a more general physiologic deficit underlies positive symptoms of schizophrenia.
The Sensitivity of [11C]Choline PET/CT to Localize Prostate Cancer Depends on the Tumor Configuration
Authors: Michael Souvatzoglou, Gregor Weirich, Sarah Schwarzenboeck, Tobias Maurer, Tibor Schuster, Ralph Alexander Bundschuh, Matthias Eiber, Ken Herrmann, Hubert Kuebler, Hans Juergen Wester, Heinz Hoefler, Juergen Gschwend, Markus Schwaiger, Uwe Treiber, Bernd Joachim Krause
Journal: Clinical Cancer Research (2011)

To evaluate the dependency of the sensitivity of [(11)C]choline positron emission tomography/computed tomography (PET/CT) for detecting and localizing primary prostate cancer (PCa) on tumor configuration in the histologic specimen.Forty-three patients with biopsy-proven PCa were included. They underwent radical prostatectomy within 31 days after [(11)C]choline PET/CT. The transaxial image slices and the histologic specimens were analyzed by comparing the respective slices. Maximum standardized uptake values (SUV(max)) were calculated in each segment and correlated with histopathology. The tumor configuration in the histologic specimen was grouped as: I, unifocal; II, multifocal; III, rind-like shaped; IV, size <5 mm. Data analysis included the investigation of detection of PCa by SUV(max), the assessment of the influence of potential contributing factors on tumor prediction, and the evaluation of whether SUV could discriminate cancer tissue from benign prostate hyperplasia (BPH), prostatitis, HGPIN (high-grade prostate intraepithelial neoplasm), or normal prostate tissue. General estimation equation models were used for statistical analysis.Tumor configuration in histology was classified as I in 21 patients, as II in 9, as III in 5, and as IV in 8. The prostate segment involved by cancer is identified in 79% of the patients. SUV(max) was located in the same side of the prostate in 95% of patients. Tumor configuration was the only factor significantly negatively influencing tumor prediction (P < 0.001). PCa-SUV(max) (median SUV(max) = 4.9) was not significantly different from BPH-SUV (median SUV(max) = 4.5) and prostatitis-SUV (median SUV(max) = 3.9), P = 0.102 and P = 0.054, respectively.The detection and localization of PCa in the prostate with [(11)C]choline PET/CT is impaired by tumor configuration. Additionally, in our patient population, PCa tissue could not be distinguished from benign pathologies in the prostate.
Assessment of the respiratory compliance in awake subjects using pressure support
Authors: R Azarian, F Lofaso, F Zerah, H Lorino, G Atlan, D Isabey, A Harf
Journal: European Respiratory Journal (1993)

Pressure support (PS), a new mode of ventilatory assistance, is known to induce respiratory muscle relaxation. It was used to obtain reliable measurements of the compliance of the respiratory system (Crs) in awake subjects. PS was applied, through a mouthpiece, at four successive levels (0, 0.75, 1 and 1.25 kPa) to 30 healthy subjects. At the highest PS level, the subject's relaxation was obtained as assessed by a decrease in the occlusion pressure from 0.10 +/- 0.06 to 0.05 +/- 0.04 kPa, whereas the minute ventilation increased (from 7.5 +/- 1.5 to 13.8 +/- 3.3 l.min-1), and the end-tidal carbon dioxide tension (PCO2) decreased (from 5.0 +/- 0.4 to 3.2 +/- 0.5 kPa) below its apnoea threshold. In three subjects, respiratory muscle relaxation was confirmed by a fall in diaphragmatic electromyographic activity. Crs was calculated as the ratio of the tidal volume to the corresponding end-inspiratory airway pressure (i.e. PS level) since, at end inspiration, a zero-flow period was obtained. Crs was highly correlated (r = 0.77) to the height (Ht) of the subjects: Crs (l.kPa-1) = 3.56 x Ht (m) -4.86 (+/- 0.23), allowing normal values to be determined. In order to evaluate the applicability of the method to patients, Crs was measured in four patients with scoliosis, and was found to range from 45-82% of the predicted values. It is suggested that this simple method of Crs determination may be used to characterize various chest wall or pulmonary diseases.
Generation of Tumor Antigen-Specific T Cell Lines from Pediatric Patients with Acute Lymphoblastic Leukemia—Implications for Immunotherapy
Authors: Gerrit Weber, Ignazio Caruana, Rayne H. Rouce, A. John Barrett, Ulrike Gerdemann, Ann M. Leen, Karen R. Rabin, Catherine M. Bollard
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Although modern cure rates for childhood acute lymphoblastic leukemia (ALL) exceed 80%, the outlook remains poor in patients with high-risk disease and those who relapse, especially when allogeneic hematopoietic stem cell transplantation is not feasible. Strategies to improve outcome and prevent relapse are therefore required. Immunotherapy with antigen-specific T cells can have antileukemic activity without the toxicities seen with intensive chemotherapy, and therefore represents an attractive strategy to improve the outcome of high-risk patients with ALL. We explored the feasibility of generating tumor antigen-specific T cells ex vivo from the peripheral blood of 50 patients with ALL [26 National Cancer Institute (NCI) high-risk and 24 standard-risk] receiving maintenance therapy. Experimental Design: Peripheral blood mononuclear cells were stimulated with autologous dendritic cells pulsed with complete peptide libraries of WT1, Survivin, MAGE-A3, and PRAME, antigens frequently expressed on ALL blasts. Results: T-cell lines were successfully expanded from all patients, despite low lymphocyte counts and irrespective of NCI risk group. Antigen-specificity was observed in more than 50% of patients after the initial stimulation and increased to more than 90% after three stimulations as assessed in IFN-γ-enzyme-linked immunospot (ELISpot) and 51Cr-release assays. Moreover, tumor-specific responses were observed by reduction of autologous leukemia blasts in short- and long-term coculture experiments. Conclusion: This study supports the use of immunotherapy with adoptively transferred autologous tumor antigen-specific T cells to prevent relapse and improve the prognosis of patients with high-risk ALL. Clin Cancer Res; 19(18); 5079–91. ©2013 AACR.
Effects of Levosimendan, a Cardiotonic Agent Targeted to Troponin C, on Cardiac Function and on Phosphorylation and Ca <sup>2+</sup> Sensitivity of Cardiac Myofibrils and Sarcoplasmic Reticulum in Guinea Pig Heart
Authors: Istvan Edes, Eva Kiss, Yoshimi Kitada, Frances M. Powers, Julius G. Papp, Evangelia G. Kranias, R. John Solaro
Journal: Circulation Research (1995)

Abstract A new cardiotonic agent, ( R )-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)-phenyl] hydrazono]propanedinitrile (Levosimendan), has been developed and screened for its ability to bind to cardiac troponin C. In perfused hearts, low concentrations of 0.03 or 0.1 μmol/L Levosimendan increased +dP/dt, but did not affect the speed of relaxation and produced only a slight increase in spontaneous heart rate in the hearts perfused with 0.1 μmol/L of the drug. In these same hearts, perfusion with 0.03 μmol/L Levosimendan did not alter the 32 P incorporation into troponin I or C protein, whereas a slight but significant increase was noted for phospholamban, with no detectable change in tissue cAMP levels. Administration of 0.1 or 0.3 μmol/L Levosimendan significantly increased myocardial cAMP levels as well as the phosphorylation of phospholamban, troponin I, and C protein. Levosimendan (0.03 to 10 μmol/L) reversibly increased force generated by detergent-extracted fiber bundles over a range of submaximally activating free Ca 2+ concentrations with no significant effect on maximum force or on Ca 2+ binding to myofilament troponin C. There was no direct effect of Levosimendan on Ca 2+ uptake by vesicles of sarcoplasmic reticulum (SR). In contrast, under conditions optimal for cAMP-dependent phosphorylation, Levosimendan slightly but significantly lowered the concentration of Ca 2+ , yielding half-maximal uptake rates by the SR vesicles. Our results indicate that at low concentrations Levosimendan acts preferably as a Ca 2+ sensitizer, whereas at higher concentrations its action as a phosphodiesterase inhibitor contributes to the positive inotropic effect.
Rapid Development of Resistance to Antifolates In Vitro: Possible Clinical Implication
Authors: A. Sobrero, C. Aschele, R. Rosso, A. Nicolin, J.R. Bertino
Journal: JNCI Journal of the National Cancer Institute (1991)

Journal Article Rapid Development of Resistance to Antifolates In Vitro: Possible Clinical Implication Get access A. Sobrero, A. Sobrero * Departments of Medical Oncology and Pharmacology, Istituto Nazionale per la Ricerca sul CancroGenoa, Italy * Correspondence to: A. Sobrero, MD, Istituto Nazionale per la Ricerca sul Cancro, Viale Benedetto XV, 10–16132, Genoa, Italy. Search for other works by this author on: Oxford Academic PubMed Google Scholar C. Aschele, C. Aschele Departments of Medical Oncology and Pharmacology, Istituto Nazionale per la Ricerca sul CancroGenoa, Italy Search for other works by this author on: Oxford Academic PubMed Google Scholar R. Rosso, R. Rosso Departments of Medical Oncology and Pharmacology, Istituto Nazionale per la Ricerca sul CancroGenoa, Italy Search for other works by this author on: Oxford Academic PubMed Google Scholar A. Nicolin, A. Nicolin Departments of Medical Oncology and Pharmacology, Istituto Nazionale per la Ricerca sul CancroGenoa, Italy Search for other works by this author on: Oxford Academic PubMed Google Scholar J.R. Bertino J.R. Bertino Memorial Sloan-Kettering Cancer CenterNew York, NY Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 83, Issue 1, 2 January 1991, Pages 24–28, https://doi.org/10.1093/jnci/83.1.24 Published: 02 January 1991 Article history Received: 01 October 1990 Accepted: 09 October 1990 Published: 02 January 1991
Induction of Therapeutically Relevant Cytotoxic T Lymphocytes in Humans by Percutaneous Peptide Immunization
Authors: Hiroaki Yagi, Hideo Hashizume, Takahiro Horibe, Yasushi Yoshinari, Maki Hata, Akihiro Ohshima, Taisuke Ito, Masahiro Takigawa, Akihiko Shibaki, Hiroshi Shimizu, Naohiro Seo
Journal: Cancer Research (2006)

Abstract Percutaneous peptide immunization (PPI) is a simple and noninvasive immunization approach to induce potent CTL responses by peptide delivery via skin with the stratum corneum removed. After such a barrier disruption in human skin, epidermal Langerhans cells, although functionally matured through the up-regulation of HLA expression and costimulatory molecules, were found to emigrate with a reduced number of dendrites. CD8+ populations binding to MHC-peptide tetramers/pentamers and producing IFN-γ appeared in the blood after PPI with HLA class I–restricted antigenic peptides. PPI with melanoma-associated peptides reduced the lesion size and suppressed further development of tumors in four of seven patients with advanced melanoma. These beneficial effects were accompanied by the generation of circulating CTLs with in vitro cytolytic activity and extensive infiltration of tetramer/pentamer-binding cells into regressing lesions. PPI elicited neither local nor systemic toxicity or autoimmunity, except for vitiligo, in patients with melanoma. Therefore, PPI represents a novel therapeutic intervention for cancer in the clinical setting. (Cancer Res 2006; 66(20): 10136-44)
Development of a Hypercoagulable Status in Patients Undergoing Off-Pump Lung Transplantation despite Prolonged Conventional Coagulation Tests
Authors: Karin Ruitenbeek, Greg C. G. Hugenholtz, Jelle Adelmeijer, Ilona T. A. Pereboom, Joost C. M. Meijers, Wim van der Bij, Robert J. Porte, Michiel E. Erasmus, Ton Lisman
Journal: American Journal of Respiratory and Critical Care Medicine (2015)