tbuckley/cabot-search huggingface dataset:
Can clinical response to cyclosporin in chronic severe asthma be predicted by an &lt;I&gt;in vitro&lt;/I&gt; T-lymphocyte proliferation assay?
Authors: A.G. Alexander, N.C. Barnes, A.B. Kay, C.J. Corrigan
Journal: European Respiratory Journal (1996)

This study tests the hypothesis that the clinical response to cyclosporin therapy of patients with chronic severe asthma is related to the sensitivity of their T-lymphocytes to the antiproliferative effects of cyclosporin in vitro. In a previous study, we observed such a relationship with glucocorticoids and the same lectin-driven proliferation assay was used in the present study. Peripheral blood mononuclear cells were obtained from 33 patients participating in a cross-over trial of oral cyclosporin therapy during both cyclosporin and placebo treatment periods, and cultured in the presence of phytohaemagglutinin and serial dilutions of cyclosporin and dexamethasone. Proliferation was measured by tritiated thymidine uptake. Both cyclosporin and dexamethasone inhibited T-lymphocyte proliferation in a concentration-dependent manner in vitro at concentrations encompassing those achieved in peripheral blood during therapy in vivo. T-lymphocytes from the asthmatic patients showed a range of sensitivity to the antiproliferative effects of cyclosporin, but this could not be correlated with improvements in peak expiratory flow rate (PEFR) or forced expiratory volume in one second (FEV1) during cyclosporin therapy as compared with placebo. In contrast to previous observations with glucocorticoids, this in vitro T-lymphocyte proliferation assay is not predictive of clinical response to cyclosporin therapy in chronic severe asthmatics.
Activation of Vitamin D Receptor by the Wilms' Tumor GeneProduct Mediates Apoptosis of Renal Cells
Authors: KAY-DIETRICH WAGNER, NICOLE WAGNER, VIKAS P. SUKHATME, HOLGER SCHOLZ
Journal: Journal of the American Society of Nephrology (2001)

Abstract. The Wilms' tumor transcription factor WT1 is required for kidney development, but little is known about WT1 downstream signaling in renal cells. This study reported an approximately fivefold upregulation of vitamin D receptor (VDR) mRNA and protein in human embryonic kidney (HEK) 293 cells that stably expressed WT1 at a level comparable to the developing kidney in vivo. Co-transfection of HEK 293 cells with expression plasmids encoding four different WT1 splicing variants stimulated mouse vdr promoter activity more than fourfold. A 201-bp fragment was identified in the proximal vdr promoter that was required for transactivation by WT1. This critical sequence contained a predicted WT1 consensus site, which bound to recombinant WT1 protein. Temporal changes of vdr and wt1 mRNA levels in developing rat kidneys were correlated closely. The active metabolite 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) strongly inhibited the proliferation of wt1-transfected HEK 293 cells. Exposure to 1,25-(OH)2D3 caused apoptosis of cultured wt1 immunopositive cells from mouse embryonic kidney cortex. These findings suggest that transcriptional activation of the VDR by WT1 can mediate programmed death of renal embryonic cells in response to 1,25-(OH)2D3. The results provide the first evidence for a role of the vitamin D endocrine system in renal cell growth and differentiation during development.
On the Hippocratic Facies
Authors: Mark A. Marinella
Journal: Journal of Clinical Oncology (2008)

Oncologists have many tools at their disposal to predict the prognosis of patients with cancer: computed tomography, magnetic resonance imaging, positron emission tomography, and various cytogenetic and molecular tests. Despite these, predicting when death will occur in an individual patient is often fraught with difficulty. Nonetheless, as patients with terminal malignancy approach death, various physical derangements may occur, such as hypopnea, apnea, an erratic pulse, cyanosis, cool extremities, and delirium. We as physicians are often approached by patient’s family members asking us to render an opinion as to when we think their loved one will die. As an example, we recently cared for a hospitalized young man with end-stage metastatic colon cancer who died while in the hospital. One morning while making rounds in the serene quiet, I studied his sunken eyes, bitemporal muscle wasting, livid skin color, and a decreased level of consciousness. This facial expression, which all oncologists frequently encounter, serves as a useful prognostic sign as described by Hippocrates centuries ago.
Reprogramming of CTLs into natural killer–like cells in celiac disease
Authors: Bertrand Meresse, Shane A. Curran, Cezary Ciszewski, Gerasim Orbelyan, Mala Setty, Govind Bhagat, Leanne Lee, Maria Tretiakova, Carol Semrad, Emily Kistner, Robert J. Winchester, Veronique Braud, Lewis L. Lanier, Daniel E. Geraghty, Peter H. Green, Stefano Guandalini, Bana Jabri
Journal: The Journal of Experimental Medicine (2006)

Celiac disease is an intestinal inflammatory disorder induced by dietary gluten in genetically susceptible individuals. The mechanisms underlying the massive expansion of interferon gamma-producing intraepithelial cytotoxic T lymphocytes (CTLs) and the destruction of the epithelial cells lining the small intestine of celiac patients have remained elusive. We report massive oligoclonal expansions of intraepithelial CTLs that exhibit a profound genetic reprogramming of natural killer (NK) functions. These CTLs aberrantly expressed cytolytic NK lineage receptors, such as NKG2C, NKp44, and NKp46, which associate with adaptor molecules bearing immunoreceptor tyrosine-based activation motifs and induce ZAP-70 phosphorylation, cytokine secretion, and proliferation independently of T cell receptor signaling. This NK transformation of CTLs may underlie both the self-perpetuating, gluten-independent tissue damage and the uncontrolled CTL expansion leading to malignant lymphomas in severe forms of celiac disease. Because similar changes were detected in a subset of CTLs from cytomegalovirus-seropositive patients, we suggest that a stepwise transformation of CTLs into NK-like cells may underlie immunopathology in various chronic infectious and inflammatory diseases.
Gefitinib Inhibits the Growth and Invasion of Urothelial Carcinoma Cell Lines in which Akt and MAPK Activation Is Dependent on Constitutive Epidermal Growth Factor Receptor Activation
Authors: Gaëlle Nicolle, Ahmad Daher, Pascale Maillé, Marcel Vermey, Sylvain Loric, Ashraf Bakkar, Hervé Wallerand, Dimitrios Vordos, Francis Vacherot, Sixtina Gil Diez de Medina, Claude C. Abbou, Theodore Van der Kwast, Jean-Paul Thiery, François Radvanyi, Dominique K. Chopin
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Abnormally high levels of epidermal growth factor receptor (EGFR) protein are associated with advanced tumor stage/grade. The objective of this study was to evaluate the effects of the specific EGFR tyrosine kinase inhibitor gefitinib on activation of the Akt and mitogen-activated protein kinase (MAPK) pathways in human urothelial cell carcinoma (UCC) cell lines and to identify potential markers of gefitinib responsiveness in biopsy samples of UCC. Experimental Design: Changes in markers of UCC growth and invasion after exposure to gefitinib were studied in six human UCC cell lines expressing various levels of EGFR. The findings were related to activation of Akt and MAPK. We studied the influence of gefitinib on intraepithelial expansion of the responsive 1207 cell line. EGFR, Akt, and MAPK activation was studied by Western blot analysis of a panel of 57 human UCC. Results: Gefitinib had a growth-inhibitory and anti-invasive effect in two of six UCC cell lines (i.e., 647V and 1207). Gefitinib was also able to block the expansion of 1207 at the expense of normal urothelial cells. These effects did not depend on the level of expression of EGFR but they were associated with the down-regulation of MAPK and Akt activity; in 1207 cells, gefitinib activity was associated with p27 up-regulation and p21 and matrix metalloproteinase-9 down-regulation. Similarly, the Akt and MAPK pathways were found to be strongly phosphorylated in association with EGFR activation in a subset of human UCC specimens. Conclusions: Activation of EGFR, Akt, and MAPK defines a subset of UCC which might provide information for the identification of gefitinib responders.
IS ENTAMOEBA HISTOLYTICA IN HOMOSEXUAL MEN A PATHOGEN?
Authors: David Goldmeier, AshleyB. Price, Owen Billington, Peter Borriello, Angela Shaw, PeterG. Sargeaunt, PatriciaE. Munday, Ian Dixon, JoannaM. Carder, Judith Hilton, DonaldJ. Jeffries
Journal: The Lancet (1986)
Overexpression of EIF5A2 promotes colorectal carcinoma cell aggressiveness by upregulating MTA1 through C-myc to induce epithelial–mesenchymaltransition
Authors: Wei Zhu, Mu-Yan Cai, Zhu-Ting Tong, Sui-Sui Dong, Shi-Juan Mai, Yi-Ji Liao, Xiu-Wu Bian, Marie C Lin, Hsiang-Fu Kung, Yi-Xin Zeng, Xin-Yuan Guan, Dan Xie
Journal: Gut (2011)

<h3>Background and Aims</h3> The authors have previously isolated a putative oncogene, eukaryotic initiation factor 5A2 (<i>EIF5A2</i>) from 3q26. In this study, <i>EIF5A2</i> was characterised for its role in colorectal carcinoma (CRC) aggressiveness and underlying molecular mechanisms. <h3>Methods</h3> The expression dynamics of EIF5A2 were examined by immunohistochemistry in a cohort of carcinomatous and non-neoplastic colorectal tissues and cells. A series of in-vivo and in-vitro assays was performed to elucidate the function of <i>EIF5A2</i> in CRC and its underlying mechanisms. <h3>Results</h3> The overexpression of EIF5A2 was examined by immunohistochemistry in 102/229 (44.5%) CRC patients, and it was significantly correlated with tumour metastasis and determined to be an independent predictor of shortened survival (p&lt;0.05). Ectopic overexpression of EIF5A2 in CRC cells enhanced cell motility and invasion in vitro and tumour metastasis in vivo, and induced epithelial–mesenchymal transition (EMT). The depletion of EIF5A2 expression prevented CRC cell invasiveness and inhibited EMT. Importantly, the metastasis-associated protein 1 (MTA1) gene was identified as a potential downstream target of EIF5A2 in CRC cells, and knockdown of MTA1 eliminated the augmentation of carcinoma cell migration, invasion and EMT by ectopic EIF5A2. The overexpression of EIF5A2 in CRC cells substantially enhanced the enrichment of c-myc on the promoter of <i>MTA1</i>, and MTA1 upregulation by EIF5A2 was partly dependent on c-myc. <h3>Conclusion</h3> The data suggest that <i>EIF5A2</i> plays an important oncogenic role in CRC aggressiveness by the upregulation of MTA1 to induce EMT, and EIF5A2 could be employed as a novel prognostic marker and/or effective therapeutic target for CRC.
PAX7 expression defines germline stem cells in the adult testis
Authors: Gina M. Aloisio, Yuji Nakada, Hatice D. Saatcioglu, Christopher G. Peña, Michael D. Baker, Edward D. Tarnawa, Jishnu Mukherjee, Hema Manjunath, Abhijit Bugde, Anita L. Sengupta, James F. Amatruda, Ileana Cuevas, F. Kent Hamra, Diego H. Castrillon
Journal: Journal of Clinical Investigation (2014)

Spermatogenesis is a complex, multistep process that maintains male fertility and is sustained by rare germline stem cells. Spermatogenic progression begins with spermatogonia, populations of which express distinct markers. The identity of the spermatogonial stem cell population in the undisturbed testis is controversial due to a lack of reliable and specific markers. Here we identified the transcription factor PAX7 as a specific marker of a rare subpopulation of Asingle spermatogonia in mice. PAX7+ cells were present in the testis at birth. Compared with the adult testis, PAX7+ cells constituted a much higher percentage of neonatal germ cells. Lineage tracing in healthy adult mice revealed that PAX7+ spermatogonia self-maintained and produced expanding clones that gave rise to mature spermatozoa. Interestingly, in mice subjected to chemotherapy and radiotherapy, both of which damage the vast majority of germ cells and can result in sterility, PAX7+ spermatogonia selectively survived, and their subsequent expansion contributed to the recovery of spermatogenesis. Finally, PAX7+ spermatogonia were present in the testes of a diverse set of mammals. Our data indicate that the PAX7+ subset of Asingle spermatogonia functions as robust testis stem cells that maintain fertility in normal spermatogenesis in healthy mice and mediate recovery after severe germline injury, such as occurs after cancer therapy.
Personal Models of Diabetes in Relation to Self-Care, Well-Being, and Glycemic Control
Authors: T. Chas Skinner, Sarah E. Hampson
Journal: Diabetes Care (2001)

Personal models of diabetes have been shown to be proximal determinants of self-care behavior in adults with diabetes, both cross-sectionally and prospectively. This study set out to test the predictive utility of this approach in adolescents with diabetes.Participants were recruited from four regional hospitals in southern England (n = 54). They completed questionnaires assessing diabetes self-care, well-being, and personal models of diabetes (perceived impact, perceived seriousness, and short- and long-term treatment effectiveness) at baseline and 1-year follow-up. GHb assays performed as part of the patients' usual diabetes care were used to assess glycemic control.After controlling for baseline anxiety, change in perceived impact of diabetes prospectively predicted adolescents' anxiety (beta = -0.21; t = -2.65; P < 0.01). After controlling for baseline dietary self-care, change in perceived effectiveness of the diabetes treatment regimen to control diabetes predicted dietary self-care (beta = -0.39; t = -3.28; P < 0.0005). Poorer dietary self-care and being female were predictive of poorer glycemic control (r2 = 0.29; F = 2.74; P < 0.005).This study provides further support for the role of personal models of illness in determining responses to illness. As adolescents take responsibility for the management of their diabetes, parents, clinicians, educators, and interventionists should consider these adolescents' beliefs about their diabetes and its treatment as key factors influencing self-care, emotional well-being. and glycemic control.
Role of thromboxane A2 in the control of myocardial O2 supply/consumption balance and severity of ischemia during pacing-induced ischemia.
Authors: G J Grover, C S Parham
Journal: Circulation Research (1989)

The role of thromboxane A2 (TXA2) in the control of O2 supply/consumption variables during pacing-induced ischemia was examined using the TXA2 receptor antagonist SQ 29,548. Anesthetized, open-chest dogs were subjected to left anterior descending coronary artery (LAD) stenosis that produced significant epicardial S-T segment elevation (12 mV) only when superimposed on atrial pacing. Regional myocardial blood flow was determined using radioactive microspheres, and O2 consumption was determined by measuring O2 saturation of venous blood draining the ischemic region. The dogs were treated with saline or 0.2 mg/kg + 0.2 mg/kg/hr SQ 29,548, and the effect on ischemia was determined during 5-minute pacing-induced ischemic episodes at 10, 40, and 70 minutes postdrug or saline treatment. SQ 29,548 significantly reduced S-T elevation at 40 and 70 minutes postdrug compared with saline values and at all times measured compared with its paired predrug pace+stenosis values. SQ 29,548 reduced S-T elevation approximately 45% compared with its paired predrug values at 70 minutes. SQ 29,548 resulted in a significantly higher subendocardial-to-subepicardial flow ratio (0.70 +/- 0.10, p less than 0.05) compared with saline-treated animals (0.42 +/- 0.06), with an overall increase of flow to the ischemic region of approximately 40%. This increased flow was matched by a proportional increase in O2 consumption without a change in O2 extraction. The O2 supply/consumption balance was also unchanged by SQ 29,548 implying that despite the increase in blood flow, the ischemic region was still flow-limited.(ABSTRACT TRUNCATED AT 250 WORDS)
Phenotype and functional evaluation of ex vivo generated antigen-specific immune effector cells with potential for therapeutic applications
Authors: Shuhong Han, Yuju Huang, Yin Liang, Yuchin Ho, Yichen Wang, Lung-Ji Chang
Journal: Journal of Hematology & Oncology (2009)

Ex vivo activation and expansion of lymphocytes for adoptive cell therapy has demonstrated great success. To improve safety and therapeutic efficacy, increased antigen specificity and reduced non-specific response of the ex vivo generated immune cells are necessary. Here, using a complete protein-spanning pool of pentadecapeptides of the latent membrane protein 2A (LMP2A) of Epstein-Barr virus (EBV), a weak viral antigen which is associated with EBV lymphoproliferative diseases, we investigated the phenotype and function of immune effector cells generated based on IFN-gamma or CD137 activation marker selection and dendritic cell (DC) activation. These ex vivo prepared immune cells exhibited a donor- and antigen-dependent T cell response; the IFN-gamma-selected immune cells displayed a donor-related CD4- or CD8-dominant T cell phenotype; however, the CD137-enriched cells showed an increased ratio of CD4 T cells. Importantly, the pentadecapeptide antigens accessed both class II and class I MHC antigen processing machineries and effectively activated EBV-specific CD4 and CD8 T cells. Phenotype and kinetic analyses revealed that the IFN-gamma and the CD137 selections enriched more central memory T (Tcm) cells than did the DC-activation approach, and after expansion, the IFN-gamma-selected effector cells showed the highest level of antigen-specificity and effector activities. While all three approaches generated immune cells with comparable antigen-specific activities, the IFN-gamma selection followed by ex vivo expansion produced high quality and quantity of antigen-specific effector cells. Our studies presented the optimal approach for generating therapeutic immune cells with potential for emergency and routine clinical applications.
Oxytocin and Reduction of Social Threat Hypersensitivity in Women With Borderline Personality Disorder
Authors: Katja Bertsch, Matthias Gamer, Brigitte Schmidt, Ilinca Schmidinger, Stephan Walther, Thorsten Kästel, Knut Schnell, Christian Büchel, Gregor Domes, Sabine C. Herpertz
Journal: American Journal of Psychiatry (2013)

Patients with borderline personality disorder are characterized by emotional hyperarousal with increased stress levels, anger proneness, and hostile, impulsive behaviors. They tend to ascribe anger to ambiguous facial expressions and exhibit enhanced and prolonged reactions in response to threatening social cues, associated with enhanced and prolonged amygdala responses. Because the intranasal administration of the neuropeptide oxytocin has been shown to improve facial recognition and to shift attention away from negative social information, the authors investigated whether borderline patients would benefit from oxytocin administration. In a randomized placebo-controlled double-blind group design, 40 nonmedicated, adult female patients with a current DSM-IV diagnosis of borderline personality disorder (two patients were excluded based on hormonal analyses) and 41 healthy women, matched on age, education, and IQ, took part in an emotion classification task 45 minutes after intranasal administration of 26 IU of oxytocin or placebo. Dependent variables were latencies and number or initial reflexive eye movements measured by eye tracking, manual response latencies, and blood-oxygen-level-dependent responses of the amygdala to angry and fearful compared with happy facial expressions. Borderline patients exhibited more and faster initial fixation changes to the eyes of angry faces combined with increased amygdala activation in response to angry faces compared with the control group. These abnormal behavioral and neural patterns were normalized after oxytocin administration. Borderline patients exhibit a hypersensitivity to social threat in early, reflexive stages of information processing. Oxytocin may decrease social threat hypersensitivity and thus reduce anger and aggressive behavior in borderline personality disorder or other psychiatric disorders with enhanced threat-driven reactive aggression.
Expression of Interleukin-18 and Caspase-1 in Cutaneous T-Cell Lymphoma
Authors: Kei-ichi Yamanaka, Rachael Clark, Rebecca Dowgiert, Daniel Hurwitz, Michio Shibata, Benjamin E. Rich, Kazuki Hirahara, David A. Jones, Sara Eapen, Hitoshi Mizutani, Thomas S. Kupper
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Cutaneous T-cell lymphoma (CTCL) is a malignancy of skin-homing Th2 T cells. Clonal T cells and CTCL skin lesions typically express Th2 cytokines, including interleukin (IL)-4, IL-5, and IL-10, but fail to produce Th1 cytokines. However, the reason for Th2 bias is unknown. IL-18 is a pleiotropic proinflammatory cytokine produced by monocytes/macrophages lineage as well as epithelial cells, such as human keratinocytes. In the absence of IL-12, IL-18 leads to increased immunoglobulin E production from B cells and enhanced production of IL-4 and IL-13 by basophils, mast cells, and CD4+ T cells. We have analyzed cytokines in CTCL patients, which may bias the immune response around the Th1/Th2 axis. Experimental Design: We examined plasma of 95 CTCL patients and skin of 20 CTCL patients for IL-18, caspase-1, IL-12, and other cytokines. To identify the presence or absence of these cytokine proteins in CTCL and normal skin, we cultured explants from skin biopsies on three-dimensional matrices. Results: Plasma levels of IL-18 and its converting enzyme, caspase-1, were significantly elevated in CTCL. mRNA levels for these factors were also elevated in CTCL skin lesions. Matrices populated with CTCL lesional skin produced significant amounts of IL-18 and caspase-1; however, production of IL-12 protein was barely detectable. Conclusions: We propose that the high levels of IL-18 expression in lesional CTCL skin contribute to increased plasma levels of IL-18 and that this, in the face of significantly lower levels of IL-12, may contribute to the Th2 bias seen in this disease.
Measurement of body surface area involvement in atopic eczema: an impossible task?
Authors: None CHARMAN, None VENN, None WILLIAMS
Journal: British Journal of Dermatology (1999)

Estimation of the area of skin involvement is an important part of atopic eczema severity scoring systems. We examine the variation seen when six dermatologically trained observers assessed disease extent in six patients with atopic eczema using the rule of nines. The median scores ranged from 4.8% to 37.2%. The level of agreement for the classification of scores into quintile categories was 55%, with a chance-corrected agreement (kappa statistic) of 0.09, representing very poor interobserver agreement. To measure the effects of health care intervention accurately, reliable methods of assessment should be used. Scoring methods in which reliability cannot be demonstrated may be misleading and should be interpreted with caution.
ERYTHROCYTE PRESERVATION. I. THE RELATION OF THE STORAGE LESION TO IN VIVO ERYTHROCYTE SENESCENCE 1
Authors: Beverly Wescott Gabrio, Clement A. Finch, Wilbur Linde, Alice Rupen
Journal: Journal of Clinical Investigation (1954)

Erythrocytes stored in an acid-citrate-dextrose preservative (ACD) at 4 to 7°C.undergo morpho-
Management of patients after self-poisoning.
Authors: R Gardner
Journal: BMJ (1980)

adults.Although vaccination of babies would be expected to increase the proportion of cases of mumps occurring in adults the absolute numbers would certainly fall if a high acceptance rate of vaccination were achieved.The need for a booster in late childhood, particularly in boys, could be met at high school at the same time as girls are given rubella immunisation.The disparity between the UK and the USA in attitudes to immunisation is curious and disturbing.