tbuckley/cabot-search huggingface dataset:
Serum CA19-9 Is Significantly Upregulated up to 2 Years before Diagnosis with Pancreatic Cancer: Implications for Early Disease Detection
Authors: Darragh P. O'Brien, Neomal S. Sandanayake, Claire Jenkinson, Aleksandra Gentry-Maharaj, Sophia Apostolidou, Evangelia-Ourania Fourkala, Stephane Camuzeaux, Oleg Blyuss, Richard Gunu, Anne Dawnay, Alexey Zaikin, Ross C. Smith, Ian J. Jacobs, Usha Menon, Eithne Costello, Stephen P. Pereira, John F. Timms
Journal: Clinical Cancer Research (2014)

Biomarkers for the early detection of pancreatic cancer are urgently needed. The primary objective of this study was to evaluate whether increased levels of serum CA19-9, CA125, CEACAM1, and REG3A are present before clinical presentation of pancreatic cancer and to assess the performance of combined markers for early detection and prognosis.This nested case-control study within the UKCTOCS included 118 single and 143 serial serum samples from 154 postmenopausal women who were subsequently diagnosed with pancreatic cancer and 304 matched noncancer controls. Samples were split randomly into independent training and test sets. CA19-9, CA125, CEACAM1, and REG3A were measured using ELISA and/or CLIA. Performance of markers to detect cancers at different times before diagnosis and for prognosis was evaluated.At 95% specificity, CA19-9 (>37 U/mL) had a sensitivity of 68% up to 1 year, and 53% up to 2 years before diagnosis. Combining CA19-9 and CA125 improved sensitivity as CA125 was elevated (>30 U/mL) in approximately 20% of CA19-9-negative cases. CEACAM1 and REG3A were late markers adding little in combined models. Average lead times of 20 to 23 months were estimated for test-positive cases. Prediagnostic levels of CA19-9 and CA125 were associated with poor overall survival (HR, 2.69 and 3.15, respectively).CA19-9 and CA125 have encouraging sensitivity for detecting preclinical pancreatic cancer, and both markers can be used as prognostic tools. This work challenges the prevailing view that CA19-9 is upregulated late in the course of pancreatic cancer development.
Off-Loading the Diabetic Foot Wound
Authors: David G. Armstrong, Hienvu C. Nguyen, Lawrence A. Lavery, Carine H.M. van Schie, Andrew J.M. Boulton, Lawrence B. Harkless
Journal: Diabetes Care (2001)

OBJECTIVE—To compare the effectiveness of total-contact casts (TCCs), removable cast walkers (RCWs), and half-shoes to heal neuropathic foot ulcerations in individuals with diabetes. RESEARCH DESIGN AND METHODS—In this prospective clinical trial, 63 patients with superficial noninfected, nonischemic diabetic plantar foot ulcers were randomized to one of three off-loading modalities: TCC, half-shoe, or RCW. Outcomes were assessed at wound healing or at 12 weeks, whichever came first. Primary outcome measures included proportion of complete wound healing at 12 weeks and activity (defined as steps per day). RESULTS—The proportions of healing for patients treated with TCC, RCW, and half-shoe were 89.5, 65.0, and 58.3%, respectively. A significantly higher proportion of patients were healed by 12 weeks in the TCC group when compared with the two other modalities (89.5 vs. 61.4%, P = 0.026, odds ratio 5.4, 95% CI 1.1–26.1). There was also a significant difference in survival distribution (time to healing) between patients treated with a TCC and both an RCW (P = 0.033) and half-shoe (P = 0.012). Patients were significantly less active in the TCC (600.1 ± 320.0 daily steps) compared with the half-shoe (1,461.8 ± 1,452.3 daily steps, P = 0.04). There was no significant difference in the average number of steps between the TCC and the RCW (767.6 ± 563.3 daily steps, P = 0.67) or the RCW and the half-shoe (P = 0.15). CONCLUSIONS—The TCC seems to heal a higher proportion of wounds in a shorter amount of time than two other widely used off-loading modalities, the RCW and the half-shoe.
CD23 antigen regulation and signaling in chronic lymphocytic leukemia.
Authors: S Fournier, G Delespesse, M Rubio, G Biron, M Sarfati
Journal: Journal of Clinical Investigation (1992)

B lymphocytes from patients with chronic lymphocytic leukemia (B-CLLs), strongly express the CD23 antigen, a surface marker with significant prognostic importance in this disease. Because we previously reported that IL-4 shows a poor capacity for CD23 expression on B-CLLs, we first examined the possible mechanisms underlying CD23 overexpression on B-CLLs and found that mitogen-activated CLL T cells release soluble factors that are capable, in synergy with IL-4, of strongly inducing CD23. Using neutralizing Abs, we noticed that the T-cell-derived enhancing activity is entirely ascribed to the combined effects of IFN gamma (potent inhibitor of CD23 on normal B cells), TNF alpha (which has no effect on normal B cells), and IL-2 (which has a slight enhancing effect on both CLL and normal B cells). Furthermore, recombinant IFN gamma as well as IFN alpha, TNF alpha, and IL-2 (but not IL-3, IL-5, IL-6, IL-7, and lymphotoxin) significantly enhance CD23 protein and mRNA expression on B-CLLs, in the presence or absence of IL-4. Inasmuch as optimal CD23 expression absolutely requires the combination of IFN gamma, IL-2, TNF alpha (the production of which is increased in CLL disease), and IL-4, it was relevant to show that IL-4 mRNA is indeed expressed in fresh T-CLL cells. We next examined the possible role of CD23 in the regulation of B-CLL proliferation. Signaling through CD23 via ligation of the antigen by F(ab')2 anti-CD23 MAb but not Fab fragments inhibits the cytokine-induced B-CLL DNA synthesis. It is concluded that the CD23 gene is abnormally regulated in B-CLL disease and that cross-linking of CD23 molecule delivers a negative growth signal to the leukemic B cells.
High-throughput microRNA profiling of pediatric high-grade gliomas
Authors: Evelina Miele, Francesca Romana Buttarelli, Antonella Arcella, Federica Begalli, Neha Garg, Marianna Silvano, Agnese Po, Caterina Baldi, Giuseppe Carissimo, Manila Antonelli, Gian Paolo Spinelli, Carlo Capalbo, Vittoria Donofrio, Isabella Morra, Paolo Nozza, Alberto Gulino, Felice Giangaspero, Elisabetta Ferretti
Journal: Neuro-Oncology (2013)

High-grade gliomas (HGGs) account for 15% of all pediatric brain tumors and are a leading cause of cancer-related mortality and morbidity. Pediatric HGGs (pHGGs) are histologically indistinguishable from their counterpart in adulthood. However, recent investigations indicate that differences occur at the molecular level, thus suggesting that the molecular path to gliomagenesis in childhood is distinct from that of adults. MicroRNAs (miRNAs) have been identified as key molecules in gene expression regulation, both in development and in cancer. miRNAs have been investigated in adult high-grade gliomas (aHGGs), but scant information is available for pHGGs. We explored the differences in microRNAs between pHGG and aHGG, in both fresh-frozen and paraffin-embedded tissue, by high-throughput miRNA profiling. We also evaluated the biological effects of miR-17-92 cluster silencing on a pHGG cell line. Comparison of miRNA expression patterns in formalin versus frozen specimens resulted in high correlation between both types of samples. The analysis of miRNA profiling revealed a specific microRNA pattern in pHGG with an overexpression and a proliferative role of the miR-17-92 cluster. Moreover, we highlighted a possible quenching function of miR-17-92 cluster on its target gene PTEN, together with an activation of tumorigenic signaling such as sonic hedgehog in pHGG. Our results suggest that microRNA profiling represents a tool to distinguishing pediatric from adult HGG and that miR-17-92 cluster sustains pHGG.
THE ROLE OF THE IKAROS GENE IN LYMPHOCYTE DEVELOPMENT AND HOMEOSTASIS
Authors: Katia Georgopoulos, Susan Winandy, Nicole Avitahl
Journal: Annual Review of Immunology (1997)

▪ Abstract The Ikaros gene, which encodes a family of hemopoietic-specific zinc finger proteins, is described as a central regulator of lymphocyte differentiation. During fetal development, it is required at the earliest stage of T cell and B cell specification. In the adult, however, lymphoid lineages rely on Ikaros at distinct phases of their development. Its activity is essential for the generation of B cell but not of T cell precursors, although the differentiation of the latter is not normal. A significant increase in CD4 thymocytes and their immediate precursors is detected, and because these cells lack markers that correlate with positive selection, a deregulation in their maturation process is suggested. Furthermore, Ikaros-null thymocytes hyperproliferate in response to T cell receptor (TCR) signaling; within days after their appearance in the thymus, clonally expanding populations are detected. Deregulated TCR-mediated responses and the fast kinetics of tumor development in these mutant thymocytes implicate Ikaros as a central tumor suppressor gene for the T cell lineage. In addition, lack of natural killer cells and selective defects in γδ T cells and dendritic antigen-presenting cells point to Ikaros as an essential factor for the establishment of early branchpoints of the T cell pathway. The dominant interference activity of Ikaros isoforms unable to bind DNA and their effects in lymphocyte development suggest that Ikaros works in concert with other factors. The role of Aiolos, a lymphoid-restricted and structurally related gene, in lymphoid differentiation is discussed. A model is proposed that defines Ikaros as the backbone of a complex regulatory protein network that controls cell fate decisions and regulates homeostasis in the hemo-lymphoid system. Changes in this regulatory network may reflect differentiation and proliferation adjustments made in hemo-lymphoid progenitors and precursors as they give rise to the cells of our immune system.
Association of joint space narrowing with impairment of physical function and work ability in patients with early rheumatoid arthritis: protection beyond disease control by adalimumab plus methotrexate
Authors: Josef S Smolen, Désirée M van der Heijde, Edward C Keystone, Ronald F van Vollenhoven, Mary B Goldring, Benoît Guérette, Mary A Cifaldi, Naijun Chen, Shufang Liu, Robert B M Landewé
Journal: Annals of the Rheumatic Diseases (2012)

Tumour necrosis factor inhibition plus methotrexate is believed to inhibit radiographic progression independent of inflammation. This analysis assessed whether these protective effects are exerted on bone (joint erosion; JE) and/or cartilage (joint space narrowing; JSN), and what the independent effects of JE/JSN progression are on longer-term patient-reported outcomes.
Potentiation of Myocardial Contractility by Continual Premature Extra-activations
Authors: Jan Koch-Weser
Journal: Circulation Research (1966)

Introduction of a premature activation into each interval between regular contractions of isolated kitten papillary muscles greatly increases isometric tension development. This premature extra-activation potentiation is a manifestation of the interval-strength relationship of ventricular myocardium and results both from the increase in the overall frequency of activation (frequency potentiation) and from the prematurity of the extra-activations (prematurity potentiation). A premature electrical stimulus which elicits a propagated action potential is always followed by a mechanically apparent activation of the contractile element. Potentiation of the regular contractions follows from the occurrence of premature, propagated action potentials, and/or the resulting activation processes. It does not depend on the extent to which the contractile element can respond to the premature activation. Prematurity potentiation results solely from an increase in the degree of activation of the contractile element. It increases over a wide range with the prematurity of the extra-activation but always decreases when the prematurity interval approaches the refractory period closely. The extent of prematurity potentiation varies with the basal frequency of contraction; it tends to raise tension development to the same high level whatever the basal frequency. Although nonpotentiated strength of contraction increases greatly with frequency, potentiated contractions at low frequencies are stronger than nonpotentiated contractions at high frequencies. At normal temperature summation of contractions plays no role in prematurity potentiation. Similarly, release of endogenous norepinephrine is not involved, but such release does occur and interferes with the study of potentiation when high-intensity stimuli are used. Premature activations may transiently alter the concentration of available Ca ++ in an intracellular site critical for activation of the contractile element.
Ventricular Dysfunction After Cardioplegic Arrest Is Improved After Myocardial Gene Transfer of a β-Adrenergic Receptor Kinase Inhibitor
Authors: Hendrik T. Tevaearai, Andrea D. Eckhart, Kyle F. Shotwell, Katrina Wilson, Walter J. Koch
Journal: Circulation (2001)

Background Acute cardiac contractile dysfunction is common after cardiopulmonary bypass (CPB). A potential molecular mechanism is enhanced β-adrenergic receptor kinase (βARK1) activity, because β-adrenergic receptor (βAR) signaling is altered in cardiomyocytes after cardioplegia. Therefore, we examined whether adenovirus-mediated intracoronary delivery of a βARK1 inhibitor (Adv-βARKct) could prevent post-CPB dysfunction. Methods and Results Rabbits were randomized to receive 5×10 11 total viral particles of Adv-βARKct or PBS. After 5 days, hearts were arrested with University of Wisconsin solution, excised, and stored at 4°C for 15 minutes or 4 hours before reperfusion on a Langendorff apparatus. Left ventricular (LV) function measured by end-diastolic pressure response to preload augmentation, contractility (LV dP/dt max ), and relaxation (LV dP/dt min ) was assessed by use of increasing doses of isoproterenol and compared with a control group of nonarrested hearts acutely perfused on the Langendorff apparatus. In the PBS-treated hearts, LV function decreased in a temporal manner and was significantly impaired compared with control hearts after 4 hours of cardioplegic arrest. LV function in Adv-βARKct-treated hearts, however, was significantly enhanced compared with PBS treatment and was similar to control nonarrested hearts even after 4 hours of cardioplegia. Biochemically, several aspects of βAR signaling were dysfunctional in PBS-treated hearts, whereas they were normalized in βARKct-overexpressing hearts. Conclusions Myocardial gene transfer of Adv-βARKct stabilizes βAR signaling and prevents LV dysfunction induced by prolonged cardioplegic arrest. Thus, βARK1 inhibition may represent a novel target in limiting depressed ventricular function after CPB.
Two-dimensional gel analysis demonstrates no structural alteration of HLA-B27 polypeptides between patients with ankylosing spondylitis and healthy individuals.
Authors: J A Trapani, I D Walker, I F McKenzie
Journal: Annals of the Rheumatic Diseases (1984)

After precipitation of the HLA-B27 antigen from the surface of peripheral blood lymphocytes (PBL) by means of an anti-HLA-B27 allospecific monoclonal antibody 2-dimensional gel electrophoresis was used to compare the structure of the B27 antigens derived from 5 patients with ankylosing spondylitis with that of healthy HLA-B27 positive counterparts. No significant difference in polypeptide structure was noted, which suggests that the pathogenesis of ankylosing spondylitis does not involve a structural alteration in cell surface HLA-B27 molecules.
T cell target 1 (TCT.1): a novel target molecule for human non-major histocompatibility complex-restricted T lymphocytes.
Authors: F Mami-Chouaib, C Miossec, P Del Porto, C Flament, F Triebel, T Hercend
Journal: The Journal of Experimental Medicine (1990)

We have studied two gamma/delta T cell clones, E102 and E117, generated in a mixed lymphocyte culture using an allogeneic Epstein-Barr virus-transformed B cell line, E418. These clones were both found to express a molecular form of T cell receptor (TCR) infrequent in human peripheral blood, associating a V1-J1-C delta chain and a V3-JP2-C2 gamma chain. Functionally, they appeared as cytotoxic T lymphocytes (CTL) with non-major histocompatibility complex (MHC) (class I and II) requiring cytotoxicity, able to kill both the immunizing (i.e., E418) and unrelated (e.g., K562, REX, F601, and KAS) target cells. A monoclonal antibody, anti-10H3, able to selectively inhibit the cytotoxic activity of the clones has been produced. This reagent defines a 43-kD molecule, designated TCT.1, with broad distribution in the hematopoietic system, that appears to be distinct from class I MHC gene products. A series of functional experiments using various effector/target cell combinations strongly suggested that TCT.1 may represent a unique TCR ligand involved in the interaction between these particular CTL clones and certain of the target cells tested, while others were likely to be recognized and killed through a TCR-independent natural killer-like pathway. Although further experimentation will be needed to strengthen our interpretation of the present data, this study provides additional evidence that some T lymphocytes, in particular of the gamma/delta type, may interact specifically with target cells in a non-MHC class I/II-requiring fashion.
RAGE and ICAM-1 cooperate in mediating leukocyte recruitment during acute inflammation in vivo
Authors: David Frommhold, Anna Kamphues, Ingrid Hepper, Monika Pruenster, Ivan K. Lukić, Ines Socher, Victoria Zablotskaya, Kirsten Buschmann, Baerbel Lange-Sperandio, Jürgen Schymeinsky, Eduard Ryschich, Johannes Poeschl, Christian Kupatt, Peter P. Nawroth, Markus Moser, Barbara Walzog, Angelika Bierhaus, Markus Sperandio
Journal: Blood (2010)
Clinical Profile and Outcome of Idiopathic Restrictive Cardiomyopathy
Authors: Naser M. Ammash, James B. Seward, Kent R. Bailey, William D. Edwards, A. Jamil Tajik
Journal: Circulation (2000)

Idiopathic restrictive cardiomyopathy is a poorly recognized entity of unknown cause characterized by nondilated, nonhypertrophied ventricles with diastolic dysfunction resulting in dilated atria and variable systolic function.Between 1979 and 1996, 94 patients (61% women) 10 to 90 years old (mean, 64 years) met strict morphological echocardiographic criteria for idiopathic restrictive cardiomyopathy, mainly dilated atria with nonhypertrophied, nondilated ventricles. None had known infiltrative disease, hypertension of >5 years' duration, or cardiac or systemic conditions associated with restrictive filling. Nineteen percent were in NYHA class I, 53% in class II, and 28% in class III or IV. Atrial fibrillation was noted in 74% of patients and systolic dysfunction in 16%. Follow-up (mean, 68 months) was complete for 93 patients (99%). At follow-up, 47 patients (50%) had died, 32 (68%) of cardiovascular causes. Four had heart transplantation. The death rate compared with actuarial statistics was significantly higher than expected (P<0.0001). Kaplan-Meier 5-year survival was 64%, compared with expected survival of 85%. Multivariate analysis using proportional hazards showed that the risk of death approximately doubles with male sex (hazard ratio [HR] = 2.1), left atrial dimension >60 mm (HR = 2.3), age >70 years (HR = 2.0), and each increment of NYHA class (HR = 2.0).Idiopathic restrictive cardiomyopathy or nondilated, nonhypertrophic ventricles with marked biatrial dilatation, as defined morphologically by echocardiography, affects predominantly elderly patients but can occur in any age group. Patients present with systemic and pulmonary venous congestion and atrial fibrillation and have a poor prognosis, particularly men >70 years old with higher NYHA class and left atrial dimension >60 mm.
CD161 (NKR-P1A) Costimulation of CD1d-dependent Activation of Human T Cells Expressing Invariant Vα24JαQ T Cell Receptor α Chains
Authors: Mark Exley, Steven Porcelli, Margo Furman, Jorge Garcia, Steven Balk
Journal: The Journal of Experimental Medicine (1998)

A population of human T cells expressing an invariant V alpha 24 J alpha Q T cell antigen receptor (TCR) alpha chain and high levels of CD161 (NKR-P1A) appears to play an immunoregulatory role through production of both T helper (Th) type 1 and Th2 cytokines. Unlike other CD161(+) T cells, the major histocompatibility complex-like nonpolymorphic CD1d molecule is the target for the TCR expressed by these T cells (V alpha 24(invt) T cells) and by the homologous murine NK1 (NKR-P1C)+ T cell population. In this report, CD161 was shown to act as a specific costimulatory molecule for TCR-mediated proliferation and cytokine secretion by V alpha 24(invt) T cells. However, in contrast to results in the mouse, ligation of CD161 in the absence of TCR stimulation did not result in V alpha 24(invt) T cell activation, and costimulation through CD161 did not cause polarization of the cytokine secretion pattern. CD161 monoclonal antibodies specifically inhibited V alpha 24(invt) T cell proliferation and cytokine secretion in response to CD1d+ target cells, demonstrating a physiological accessory molecule function for CD161. However, CD1d-restricted target cell lysis by activated V alpha 24(invt) T cells, which involved a granule-mediated exocytotic mechanism, was CD161-independent. In further contrast to the mouse, the signaling pathway involved in V alpha 24(invt) T cell costimulation through CD161 did not appear to involve stable association with tyrosine kinase p56(Lck). These results demonstrate a role for CD161 as a novel costimulatory molecule for TCR-mediated recognition of CD1d by human V alpha 24(invt) T cells.
Lack of Comprehension of Common Prostate Cancer Terms in an Underserved Population
Authors: Kerry L. Kilbridge, Gertrude Fraser, Murray Krahn, Elizabeth M. Nelson, Mark Conaway, Randall Bashore, Andrew Wolf, Michael J. Barry, Debra A. Gong, Robert F. Nease, Alfred F. Connors
Journal: Journal of Clinical Oncology (2009)

To assess the comprehension of common medical terms used in prostate cancer in patient education materials to obtain informed consent, and to measure outcomes after prostate cancer treatment. We address this issue among underserved, African-American men because of the increased cancer incidence and mortality observed in this population.
Gastroprotective effect of ranitidine bismuth citrate is associated with increased mucus bismuth concentration in rats.
Authors: S Tanaka, P H Guth, G Paulsen, J D Kaunitz
Journal: Gut (1996)

Antisecretory and bismuth compounds protect the gastric mucosa from injury resulting from non-steroidal anti-inflammatory drugs.To study the mechanism underlying the gastroprotective effects of ranitidine bismuth citrate (GG311) in rats.Indomethacin rat injury model and in vivo microscopy in which acid output, surface cell intracellular pH (pHi), gastric mucus gel thickness, and mucosal blood flow were measured simultaneously.In injury studies, GG311 dose dependently protected against severe injury induced by indomethacin (60 mg/kg subcutaneously). In in vivo microscopic studies, indomethacin significantly decreased mucus gel thickness and increased the initial rate of acidification of gastric surface cells when the superfusate pH was lowered from 7.4 to 1.0, and impaired pHi during acid exposure. Indomethacin had no effect on mucosal blood flow or acid output. GG311 alone had no effect on gel thickness, blood flow, or pHi homeostasis during acid exposure, but improved the initial acidification rate and pHi during superfusion with pH 1.0 solutions in the presence of indomethacin. In separate experiments, indomethacin pretreatment considerably increased gastric mucus bismuth concentrations in rats given GG311.The gastroprotective effect of GG311 against indomethacin induced gastric injury is associated with high and prolonged gastric mucus bismuth concentrations, which may impair proton permeation across the mucus gel.