tbuckley/cabot-search huggingface dataset:
Preliminary Efficacy of the Anti-Insulin–Like Growth Factor Type 1 Receptor Antibody Figitumumab in Patients With Refractory Ewing Sarcoma
Authors: Heribert Juergens, Najat C. Daw, Birgit Geoerger, Stefano Ferrari, Milena Villarroel, Isabelle Aerts, Jeremy Whelan, Uta Dirksen, Mary L. Hixon, Donghua Yin, Tao Wang, Stephanie Green, Luisa Paccagnella, Antonio Gualberto
Journal: Journal of Clinical Oncology (2011)

Patients with Ewing sarcoma (ES) with metastases and those who relapse fare poorly and receive therapies that carry significant toxicity. This phase 1/2 study was conducted to evaluate the efficacy of figitumumab in advanced ES.Patients with sarcoma 10 to 18 years old were enrolled in two dose escalation cohorts (20 and 30 mg/Kg intravenously every 4 weeks) in the phase 1 portion of the study. Patients with ES 10 years old or older were enrolled in the phase 2 portion of the study. The primary phase 2 objective was objective response rate (ORR).Thirty-one patients with ES (n = 16), osteosarcoma (n = 11), or other sarcomas (n = 4) were enrolled in the phase 1 portion of the study. Dose escalation proceeded to 30 mg/kg every 4 weeks with no dose-limiting toxicity identified. In the phase 2 portion of the study, 107 patients with ES received figitumumab at 30 mg/kg every 4 weeks for a median of 2 cycles (range, 1 to 16). Sixty three percent of phase 2 patients had received at least three prior treatment regimens. Of 106 evaluable patients, 15 had a partial response (ORR, 14.2%) and 25 had stable disease. Median overall survival was 8.9 months. Importantly, patients with a pretreatment circulating free insulin-like growth factor (IGF) -1 lower than 0.65 ng/mL (n = 14) had a median OS of 3.6 months, whereas those with a baseline free IGF-1 ≥ 0.65 ng/mL (n = 84) had a median OS of 10.4 months (P < .001).Figitumumab had modest activity as single agent in advanced ES. A strong association between pretreatment serum IGF-1 and survival benefit was identified.
Genome-wide identification of functionally distinct subsets of cellular mRNAs associated with two nucleocytoplasmic-shuttling mammalian splicing factors.
Authors: Margarida Gama-Carvalho, Nuno L Barbosa-Morais, Alexander S Brodsky, Pamela A Silver, Maria Carmo-Fonseca
Journal: Genome biology (2006)

Pre-mRNA splicing is an essential step in gene expression that occurs co-transcriptionally in the cell nucleus, involving a large number of RNA binding protein splicing factors, in addition to core spliceosome components. Several of these proteins are required for the recognition of intronic sequence elements, transiently associating with the primary transcript during splicing. Some protein splicing factors, such as the U2 small nuclear RNP auxiliary factor (U2AF), are known to be exported to the cytoplasm, despite being implicated solely in nuclear functions. This observation raises the question of whether U2AF associates with mature mRNA-ribonucleoprotein particles in transit to the cytoplasm, participating in additional cellular functions.Here we report the identification of RNAs immunoprecipitated by a monoclonal antibody specific for the U2AF 65 kDa subunit (U2AF65) and demonstrate its association with spliced mRNAs. For comparison, we analyzed mRNAs associated with the polypyrimidine tract binding protein (PTB), a splicing factor that also binds to intronic pyrimidine-rich sequences but additionally participates in mRNA localization, stability, and translation. Our results show that 10% of cellular mRNAs expressed in HeLa cells associate differentially with U2AF65 and PTB. Among U2AF65-associated mRNAs there is a predominance of transcription factors and cell cycle regulators, whereas PTB-associated transcripts are enriched in mRNA species that encode proteins implicated in intracellular transport, vesicle trafficking, and apoptosis.Our results show that U2AF65 associates with specific subsets of spliced mRNAs, strongly suggesting that it is involved in novel cellular functions in addition to splicing.
Calcium current is increased in isolated adult myocytes from hypertrophied rat myocardium.
Authors: E C Keung
Journal: Circulation Research (1989)

To study the effects of myocardial hypertrophy resulting from chronic pressure overload on excitation-contraction coupling, the cardiac transmembrane L-type calcium current (ICa) was investigated in the Goldblatt renovascular hypertensive (HBP) rat. ICa was measured in single myocytes enzymatically isolated from control (CTRL) and HBP rat hearts using the whole-cell, patch-clamp method. The peak ICa and ICa density (obtained by normalizing ICa to the average cell capacitative surface area) were larger in HBP cells (n = 15) than in CTRL cells (n = 10) at membrane potentials of -20 to 50 mV (p less than 0.01). The maximal peak ICa increased from 0.9 +/- 0.5 nA (mean +/- SD) in CTRL cells to 2.8 +/- 1.0 nA in HBP cells (p less than 0.001). The corresponding ICa density increased from 5.3 +/- 2.7 to 16.2 +/- 6.0 microA/cm2 (p less than 0.001). There was no shift in the current-voltage relation between CTRL and HBP cells. The time course of decay of HBP ICa in response to clamp steps to the plateau range of the action potential (membrane potential, Vm = -10 to 30 mV) was delayed when compared with that of CTRL ICa. The inactivation time constants (biexponential) for the maximal ICa were 6.9 +/- 1.9 and 36.0 +/- 9.3 msec for CTRL cells and 6.7 +/- 1.4 and 49.5 +/- 12.9 msec for HBP cells (p less than 0.05 for the slower component of the maximal ICa). There was no difference in the steady-state inactivation of ICa (f infinity) for the CTRL and HBP cells. From the maximal peak ICa, cytoplasmic free Ca2+ was estimated to reach a pCa of 6.95 +/- 0.07 for CTRL cells and 6.64 +/- 0.13 for HBP cells. It is concluded that ICa is increased with myocardial hypertrophy. The lengthening of the action potential in hypertrophied rat myocardium is due to an increase in peak current density and to the slower inactivation of the maximal ICa. The increased transmembrane flux of Ca2+ via ICa in HBP cells is inadequate to achieve a myoplasmic free Ca2+ level sufficient for direct partial activation of the contractile myofilaments. However, in the scheme of the calcium-triggered calcium release hypothesis such an increase could provide an increased amount of activator calcium and/or serve to amplify the release of Ca2+ from sarcoplasmic reticulum, thereby contributing to preserved peak developed tension in hypertrophied rat myocardium.
An Alternative Open Reading Frame of the Human Macrophage Colony-Stimulating Factor Gene Is Independently Translated and Codes for an Antigenic Peptide of 14 Amino Acids Recognized by Tumor-Infiltrating Cd8 T Lymphocytes
Authors: Michael Probst-Kepper, Vincent Stroobant, Robert Kridel, Béatrice Gaugler, Claire Landry, Francis Brasseur, Jean-Pierre Cosyns, Birgit Weynand, Thierry Boon, Benoit J. Van den Eynde
Journal: The Journal of Experimental Medicine (2001)

We show that cytotoxic T lymphocytes (CTLs) infiltrating a kidney tumor recognize a peptide encoded by an alternative open reading frame (ORF) of the macrophage colony-stimulating factor (M-CSF) gene. Remarkably, this alternative ORF, which is translated in many tumors concurrently with the major ORF, is also translated in some tissues that do not produce M-CSF, such as liver and kidney. Such a dissociation of the translation of two overlapping ORFs from the same gene is unexpected. The antigenic peptide encoded by the alternative ORF is presented by human histocompatibility leukocyte antigen (HLA)-B*3501 and has a length of 14 residues. Peptide elution indicated that tumor cells naturally present this 14 mer, which is the longest peptide known to be recognized by CTLs. Binding studies of peptide analogues suggest that it binds by its two extremities and bulges out of the HLA groove to compensate for its length.
Serum β-2 Microglobulin Levels Predict Mortality in Dialysis Patients
Authors: Alfred K. Cheung, Michael V. Rocco, Guofen Yan, John K. Leypoldt, Nathan W. Levin, Tom Greene, Lawrence Agodoa, James Bailey, Gerald J. Beck, William Clark, Andrew S. Levey, Daniel B. Ornt, Gerald Schulman, Steven Schwab, Brendan Teehan, Garabed Eknoyan
Journal: Journal of the American Society of Nephrology (2005)

In the randomized Hemodialysis (HEMO) Study, chronic high-flux dialysis, as defined by higher beta-2 microglobulin (beta(2)M) clearance, compared with low-flux dialysis did not significantly alter all-cause mortality in the entire cohort but was associated with lower mortality in long-term dialysis patients. This analysis examined the determinants of serum beta(2)M levels and the associations of serum beta(2)M levels or dialyzer beta(2)M clearance with mortality. In a multivariable regression model that examined 1704 patients, baseline residual kidney urea clearance and dialyzer beta(2)M clearance were strong predictors of predialysis serum beta(2)M levels at 1 mo of follow-up, with regression coefficients of -7.21 (+/-0.69 SE) mg/L per ml/min per 35 L urea volume (P < 0.0001) and -1.94 (+/-0.30) mg/L per ml/min (P < 0.0001),respectively. In addition, black race and baseline years on dialysis correlated positively whereas age, diabetes, serum albumin, and body mass index correlated negatively with serum beta(2)M levels (P < 0.05). In time-dependent Cox regression models, mean cumulative predialysis serum beta(2)M levels but not dialyzer beta(2)M clearance were associated with all-cause mortality (relative risk = 1.11 per 10-mg/L increase in beta(2)M level; 95% confidence interval 1.05 to 1.19; P = 0.001), after adjustment for residual kidney urea clearance and number of prestudy years on dialysis. This association is supportive of the potential value of beta(2)M as a marker to guide chronic hemodialysis therapy.
Tamoxifen: Trials, Tribulations, and Trade-offs
Authors: Michael A. Friedman, Edward L. Trimble, Jeffrey S. Abrams
Journal: JNCI Journal of the National Cancer Institute (1994)

Journal Article Tamoxifen: Trials, Tribulations, and Trade-offs Get access Michael A. Friedman, Michael A. Friedman Search for other works by this author on: Oxford Academic PubMed Google Scholar Edward L. Trimble, Edward L. Trimble Search for other works by this author on: Oxford Academic PubMed Google Scholar Jeffrey S. Abrams Jeffrey S. Abrams Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 86, Issue 7, 6 April 1994, Pages 478–479, https://doi.org/10.1093/jnci/86.7.478 Published: 06 April 1994 Article history Received: 11 March 1994 Accepted: 15 March 1994 Published: 06 April 1994
Minimal Functional β-Cell Mass in Intraportal Implants That Reduces Glycemic Variability in Type 1 Diabetic Recipients
Authors: Pieter Gillard, Robert Hilbrands, Ursule Van de Velde, Zhidong Ling, Da Hae Lee, Ilse Weets, Frans Gorus, Christophe De Block, Leonard Kaufman, Chantal Mathieu, Daniel Pipeleers, Bart Keymeulen
Journal: Diabetes Care (2013)

OBJECTIVE Previous work has shown a correlation between β-cell number in cultured islet cell grafts and their ability to induce C-peptide secretion after intraportal implantation in C-peptide–negative type1 diabetic patients. In this cross-sectional study, we examined the minimal functional β-cell mass (FBM) in the implant that induces metabolic improvement. RESEARCH DESIGN AND METHODS Glucose clamps assessed FBM in 42 recipients with established implants. C-peptide release during each phase was expressed as percentage of healthy control values. Its relative magnitude during a second hyperglycemic phase was most discriminative and therefore selected as a parameter to be correlated with metabolic effects. RESULTS Recipients with functioning β-cell implants exhibited average FBM corresponding to 18% of that in normal control subjects (interquartile range 10–33%). Its relative magnitude negatively correlated with HbA1c levels (r = −0.47), daily insulin dose (r = −0.75), and coefficient of variation of fasting glycemia (CVfg) (r = −0.78, retained in multivariate analysis). A correlation between FBM and CVfg &amp;lt;25% appeared from the receiver operating characteristic curve (0.97 [95% CI 0.93–1.00]). All patients with FBM &amp;gt;37% exhibited CVfg &amp;lt;25% and a &amp;gt;50% reduction of their pretransplant CVfg; this occurred in none with FBM &amp;lt;5%. Implants with FBM &amp;gt;18% reduced CVfg from a median pretransplant value of 46 to &amp;lt;25%. CONCLUSIONS Glucose clamping assesses the degree of restoration in FBM achieved by islet cell implants. Values &amp;gt;37% of normal control subjects appear needed to reduce glycemic variability in type 1 diabetic recipients. Further studies should examine whether the test can help guide decisions on additional islet cell transplants and on adjusting or stopping immunotherapy.
Trends of skin diseases in organ-transplant recipients transplanted between 1966 and 2006: a cohort study with follow-up between 1994 and 2006
Authors: H.C. Wisgerhof, J.R.J. Edelbroek, J.W. De Fijter, M.C.W. Feltkamp, R. Willemze, J.N. Bouwes Bavinck
Journal: British Journal of Dermatology (2009)

Skin diseases are frequently observed in organ-transplant recipients (OTRs).To count the registered skin diseases in all 2136 OTRs who had been transplanted in a single centre between 1966 and 2006 and to calculate their relative contribution in relation to the number of years after transplantation.All registered skin diseases which were entered into a computerized system between 1994 and 2006 at the Leiden University Medical Centre were counted and their relative contributions were calculated.Between 1994 and 2006, 2408 skin diseases were registered in 801 of 1768 OTRs who were at risk during this specific time period. The most commonly recorded diagnoses were skin infections (24.0%) followed by benign skin tumours (23.3%) and malignant skin lesions (18.2%). The relative contributions of infectious and inflammatory disorders decreased with time after transplantation, whereas the contribution of squamous cell carcinomas strongly increased with time.This study gives a systematic overview of the high burden of skin diseases in OTRs. The relative distributions of skin diseases importantly changed with time after transplantation, with squamous cell carcinoma contributing most to the increasing burden of skin diseases with increasing time after transplantation.
Effect of Changes in Frequency of Stimulation Upon Rabbit Ventricular Action Potential
Authors: COLIN L. GIBBS, EDWARD A. JOHNSON
Journal: Circulation Research (1961)

It has been demonstrated that in rabbit ventricular muscle, the area of the action potential is at a maximum at a stimulus frequency ranging from 1 to 3 sec. -1 . At frequencies on either side of this range the action potential decreases in area. The changes in action-potential shape at high rates of stimulation are caused by an earlier "take off" of the fast phase of repolarization, and at low rates of stimulation the changes in shape are predominantly caused by a drop in the height of the plateau. It has also been shown that the ratio of the area of the extra action potential to the area of the normal action potential depends upon the stimulus frequency and the interval between the normal and extra action potentials. Upon any chauge in the stimulus frequency, the area of the ventricular action potential overshoots its final value before stabilizing. The shape of the action potential is dependent upon the previous history of the muscle. By altering the frequency of stimulation, it has also been shown that the changes in action-potential shape at low frequencies of stimulation, in contrast to those at high frequencies, are very rapid and take place immediately when the basic stimulus frequency is altered.
Mortality at 1 Year With Combination Platelet Glycoprotein IIb/IIIa Inhibition and Reduced-Dose Fibrinolytic Therapy vs Conventional Fibrinolytic Therapy for Acute Myocardial Infarction
Authors: A Michael Lincoff, Robert M Califf, Frans Van de Werf, James T Willerson, Harvey D White, Paul W Armstrong, Victor Guetta, W Brian Gibler, Judith S Hochman, Christoph Bode, Alec Vahanian, P Gabriel Steg, Diego Ardissino, Stefano Savonitto, Frits Bar, Zygmunt Sadowski, Amadeo Betriu, Joan E Booth, Kathy Wolski, Michael Waller, Eric J Topol
Journal: JAMA (2002)

Among patients with acute myocardial infarction, combination reperfusion therapy with a platelet glycoprotein IIb/IIIa receptor inhibitor (abciximab) and a half dose of a plasminogen activator (reteplase) did not significantly reduce mortality at 30 days compared with a full dose of reteplase. Rates of nonfatal ischemic complications were significantly diminished.To determine if the beneficial effects of abciximab and reteplase (combination therapy) on early nonfatal complications would translate into a reduction in the risk of death by 1 year.One-year follow-up of a randomized controlled trial (Global Use of Strategies To Open Coronary Arteries [GUSTO] V). Of 16 588 patients who had been treated in 820 community and referral hospitals in 20 countries between July 1999 and February 2001, mortality data were available for 16 453 (99.2%).Patients were randomly assigned to receive (intravenously) a standard dose of reteplase (two 10-U boluses, 30 minutes apart) or the combination of a standard dose of abciximab (0.25 mg/kg bolus, 0.125 microg/kg per minute infusion [maximum 10 micro g/min for 12 hours]) and a half dose of reteplase (two 5-U boluses, 30 minutes apart).One-year all-cause mortality rates.All-cause mortality at 1 year occurred in 692 (8.38%) of 8260 patients in the reteplase group and 698 (8.38%) of the 8328 patients in the combination therapy group (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.90-1.11; P>.99). Reinfarction within the first 7 days occurred in 3.5% of patients in the reteplase group and 2.3% of patients in the combination therapy group, and was significantly associated with 1-year mortality (22.6% in patients with reinfarction vs 8.0% in patients without reinfarction; HR, 3.08; 95% CI, 2.53-3.75; P<.001). However, treatment assignment did not significantly influence time of mortality regardless of reinfarction status.Combination therapy (abciximab and reteplase) did not reduce mortality over 1 year compared with fibrinolytic therapy with reteplase alone.
Concurrent chemo- and radiotherapy in patients with locally advanced carcinoma of the cervix
Authors: E. Pras, P.H.B. Willemse, H. Boonstra, H. Hollema, M.A.A.M. Heesters, B.G. Szabó, H.W.A. de Bruijn, J.G. Aalders, E.G.E. de Vries
Journal: Annals of Oncology (1996)
CC Chemokine Ligand 18 in ANCA-Associated Crescentic GN
Authors: Silke R. Brix, Gesa Stege, Erik Disteldorf, Elion Hoxha, Christian Krebs, Sonja Krohn, Benjamin Otto, Kristin Klätschke, Elisabeth Herden, Felix Heymann, Sergio A. Lira, Frank Tacke, Gunter Wolf, Martin Busch, Wolfram J. Jabs, Fedai Özcan, Frieder Keller, Joachim Beige, Karl Wagner, Udo Helmchen, Mercedes Noriega, Thorsten Wiech, Ulf Panzer, Rolf A.K. Stahl
Journal: Journal of the American Society of Nephrology (2015)

ANCA-associated vasculitis is the most frequent cause of crescentic GN. To define new molecular and/or cellular biomarkers of this disease in the kidney, we performed microarray analyses of renal biopsy samples from patients with ANCA-associated crescentic GN. Expression profiles were correlated with clinical data in a prospective study of patients with renal ANCA disease. CC chemokine ligand 18 (CCL18), acting through CC chemokine receptor 8 (CCR8) on mononuclear cells, was identified as the most upregulated chemotactic cytokine in patients with newly diagnosed ANCA-associated crescentic GN. Macrophages and myeloid dendritic cells in the kidney were detected as CCL18-producing cells. The density of CCL18+ cells correlated with crescent formation, interstitial inflammation, and impairment of renal function. CCL18 protein levels were higher in sera of patients with renal ANCA disease compared with those in sera of patients with other forms of crescentic GN. CCL18 serum levels were higher in patients who suffered from ANCA-associated renal relapses compared with those in patients who remained in remission. Using a murine model of crescentic GN, we explored the effects of the CCL18 murine functional analog CCL8 and its receptor CCR8 on kidney function and morphology. Compared with wild-type mice, Ccr8−/− mice had significantly less infiltration of pathogenic mononuclear phagocytes. Furthermore, Ccr8−/− mice maintained renal function better and had reduced renal tissue injury. In summary, our data indicate that CCL18 drives renal inflammation through CCR8-expressing cells and could serve as a biomarker for disease activity and renal relapse in ANCA-associated crescentic GN.
Serum Blood Urea Nitrogen as an Independent Marker of Subsequent Mortality Among Patients With Acute Coronary Syndromes and Normal to Mildly Reduced Glomerular Filtration Rates
Authors: Ajay J. Kirtane, David M. Leder, Sushrut S. Waikar, Glenn M. Chertow, Kausik K. Ray, Duane S. Pinto, Dimitrios Karmpaliotis, Andrew J. Burger, Sabina A. Murphy, Christopher P. Cannon, Eugene Braunwald, C. Michael Gibson
Journal: Journal of the American College of Cardiology (2005)
Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions
Authors: Gerard Lozanski, Nyla A. Heerema, Ian W. Flinn, Lisa Smith, Jennifer Harbison, Jennifer Webb, Mollie Moran, Margaret Lucas, Thomas Lin, Marcy L. Hackbarth, John H. Proffitt, David Lucas, Michael R. Grever, John C. Byrd
Journal: Blood (2004)
MDR1 gene–related clonal selection and P-glycoprotein function and expression in relapsed or refractory acute myeloid leukemia
Authors: Marry M. van den Heuvel-Eibrink, Erik A. C. Wiemer, Marjan J. de Boevere, Bronno van der Holt, Paula J. M. Vossebeld, Rob Pieters, Pieter Sonneveld
Journal: Blood (2001)
Modulation of transforming growth factor beta function in hepatocytes and hepatic stellate cells in rat liver injury
Authors: M Date
Journal: Gut (2000)

<h3>BACKGROUND</h3> Transforming growth factor β (TGF-β) regulates hepatocyte proliferation and biosynthesis of the extracellular matrix. <h3>AIMS</h3> This study investigated alternations in sensitivity to TGF-β1 and binding properties for ligand in hepatocytes and hepatic stellate cells (HSC) after CCl<sub>4</sub> administration. <h3>METHODS</h3> Plasma TGF-β1 levels in rats after CCl<sub>4</sub> administration were determined using ELISA. Effects of TGF-β1 were examined by DNA synthesis in hepatocytes and by measurement of fibronectin production in HSC after CCl<sub>4</sub> administration. Binding of<sup>125</sup>I TGF-β1 was tested in these cells. <h3>RESULTS</h3> Plasma TGF-β1 levels were increased as early as 24 hours and were maximal by 48 hours . The antiproliferative response to TGF-β1 decreased in hepatocytes at 48 hours and normalised at 72 hours. Fibronectin production of both normal and injured HSC was affected by TGF-β1 treatment. Cross linked ligand/receptor complexes were detected in normal hepatocytes and HSC. However, these levels decreased specifically in hepatocytes at 48 hours and normalised by 72 hours. <h3>CONCLUSIONS</h3> Downregulation of TGF-β receptor occurred in hepatocytes after chemical insult and TGF-β1 could not transduce its antiproliferative signal. Recovery of TGF-β receptor expression causes the signal to transduce to the nucleus at 72 hours. In HSC, whenever TGF-β1 is increased, TGF-β1 can transduce its signal for fibronectin production via its receptor because signalling receptors are expressed constantly.