tbuckley/cabot-search huggingface dataset:
Proinflammatory Characteristics of SMAC/DIABLO-Induced Cell Death in Antitumor Therapy
Authors: Perpetua U. Emeagi, Sandra Van Lint, Cleo Goyvaerts, Sarah Maenhout, Anje Cauwels, Iain A. McNeish, Tomas Bos, Carlo Heirman, Kris Thielemans, Joeri L. Aerts, Karine Breckpot
Journal: Cancer Research (2012)

Molecular mimetics of the caspase activator second mitochondria-derived activator of caspase (SMAC) are being investigated for use in cancer therapy, but an understanding of in vivo effects remains incomplete. In this study, we offer evidence that SMAC mimetics elicit a proinflammatory cell death in cancer cells that engages an adaptive antitumor immune response. Cancer cells of different histologic origin underwent apoptosis when transduced with lentiviral vectors encoding a cytosolic form of the SMAC mimetic LV-tSMAC. Strikingly, treatment of tumor-bearing mice with LV-tSMAC resulted in the induction of apoptosis, activation of antitumor immunity, and enhanced survival. Antitumor immunity was accompanied by an increase of tumor-infiltrating lymphocytes displaying low PD-1 expression, high lytic capacity, and high levels of IFN-γ when stimulated. We also noted in vivo a decrease in regulatory T cells along with in vitro activation of tumor-specific CD8(+) T cells by dendritic cells (DC) isolated from tumor draining lymph nodes. Last, tumor-specific cytotoxic T cells were also found to be activated in vivo. Mechanistic analyses showed that transduction of cancer cells with LV-tSMAC resulted in exposure of calreticulin but not release of HMGB1 or ATP. Nevertheless, DCs were activated upon engulfment of dying cancer cells. Further validation of these findings was obtained by their extension in a model of human melanoma using transcriptionally targeted LV-tSMAC. Together, our findings suggest that SMAC mimetics can elicit a proinflammatory cell death that is sufficient to activate adaptive antitumor immune responses in cancer.
RUNX1 DNA-Binding Mutants, Associated with Minimally Differentiated Acute Myelogenous Leukemia, Disrupt Myeloid Differentiation
Authors: Jörg Cammenga, Birte Niebuhr, Stefan Horn, Ulla Bergholz, Gabriele Putz, Frank Buchholz, Jürgen Löhler, Carol Stocking
Journal: Cancer Research (2007)

Abstract Mutations in the RUNX1 gene are found at high frequencies in minimally differentiated acute myelogenous leukemia. In addition to null mutations, many of the mutations generate Runx1 DNA-binding (RDB) mutants. To determine if these mutants antagonize wild-type protein activity, cDNAs were transduced into murine bone marrow or human cord blood cells using retroviral vectors. Significantly, the RDB mutants did not act in a transdominant fashion in vivo to disrupt Runx1 activity in either T-cell or platelet development, which are highly sensitive to Runx1 dosage. However, RDB mutant expression impaired expansion and differentiation of the erythroid compartment in which Runx1 expression is normally down-regulated, showing that a RDB-independent function is incompatible with erythroid differentiation. Significantly, both bone marrow progenitors expressing RDB mutants or deficient for Runx1 showed increased replating efficiencies in vitro, accompanied by the accumulation of myeloblasts and dysplastic progenitors, but the effect was more pronounced in RDB cultures. Disruption of the interface that binds CBFβ, an important cofactor of Runx1, did not impair RDB mutant replating activity, arguing against inactivation of Runx1 function by CBFβ sequestration. We propose that RDB mutants antagonize Runx1 function in early progenitors by disrupting a critical balance between DNA-binding–independent and DNA-binding–dependent signaling. [Cancer Res 2007;67(2):537–45]
Ionized Magnesium in Danish Children With Type 1 Diabetes
Authors: Gitte Matthiesen, Kern Olofsson, Martin Rudnicki
Journal: Diabetes Care (2004)

It is well known that type 1 diabetes is associated with magnesium deficiency (1), which may be followed by vascular complications (2–5). As a consequence, magnesium supplementation has been advocated to diabetic patients to minimize the risk of serious complications (6–8). The magnitude of hypomagnesemia in diabetic subjects is, however, difficult to establish because most studies have reported changes in total magnesium (i.e., ionized magnesium bound to albumin and other ligands), whereas only sparse information is available regarding ionized ion (9–11). Recently, a new electrode has been available for the measurement of ionized magnesium (12,13).

The aim of the present investigation was to test the hypothesis that the level of ionized magnesium was lower in diabetic children and related to poor glycemic control.

In total, 81 children with type 1 diabetes were included prospectively from September 1999 to May 2000. Inclusion criteria were age <18 years, duration of diabetes <3 months, and an equal distribution in the age-groups: 0–5, 6–11, and 12–17 years. All children were treated with diet and one to three daily injections of short- and intermediate-acting insulin. Exclusion criteria were …
Decreased expression of the long non-coding RNA FENDRR is associated with poor prognosis in gastric cancer and FENDRR regulates gastric cancer cell metastasis by affecting fibronectin1 expression
Authors: Tong-peng Xu, Ming-de Huang, Rui Xia, Xin-xin Liu, Ming Sun, Li Yin, Wen-ming Chen, Liang Han, Er-bao Zhang, Rong Kong, Wei De, Yong-qian Shu
Journal: Journal of Hematology & Oncology (2014)

FENDRR is a long non-coding RNAs (lncRNA) that binds to polycomb repressive complexe 2 (PRC2) to epigenetically regulate the expression of its target gene. The clinical role of FENDRR in carcinomas remains yet to be found.Real-time polymerase chain reaction (PCR) was used to examine FENDRR expression in gastric cancer cell lines/tissues compared with normal epithelial cells/adjacent non-tumorous tissues. Cell proliferation assays, Wound healing assays, and in vitro and in vivo invasion and migration assays were performed to detect the biological effects of FENDRR in gastric cancer cells. Real-time PCR, western-blot and immunohistochemistry were used to evaluate the mRNA and protein expression of fibronectin1 (FN1). Secreted matrix metalloproteinase (MMP) activities were detected and characterized using gelatin zymography assay.FENDRR was downregulated in gastric cancer cell lines and cancerous tissues, as compared with normal gastric epithelial cells and adjacent noncancerous tissue samples. Low FENDRR expression was correlated with deeper tumor invasion (p < 0.001), higher tumor stage (p = 0.001), and lymphatic metastasis (p = 0.007). Univariate and multivariate analyses indicated that low FENDRR expression predicted poor prognosis. Histone deacetylation was involved in the downregulation of FENDRR in gastric cancer cells. FENDER overexpression suppressed invasion and migration by gastric cancer cells in vitro, by downregulating FN1 and MMP2/MMP9 expression.Low expression of the lncRNA FENDRR occurs in gastric cancer and is associated with poor prognosis. Thus, FENDRR plays an important role in the progression and metastasis of gastric cancer.
Experimental and Clinical Evaluation in Man of Hexamethonium (C6), A New Ganglionic Blocking Agent
Authors: FRANK A. FINNERTY, EDWARD D. FREIS
Journal: Circulation (1950)

In man, C6, a new ganglionic blocking agent (50 mg. intravenously) produced inhibition of the Valsalva, tiltback and cold pressor vasopressor responses. Marked increases in digital blood flow and skin temperature with inhibition of digital reflexes to "noxious" stimuli were consistently observed (room temperature 70 F.). The increase in skin temperature was greater and more lasting than following Priscoline or tetraethylammonium chloride. Except for severe postural hypotension, side effects were minimal. Clinically the drug may be useful in the evaluation of sympathetic vasoconstriction in peripheral vascular disease as well as in the treatment of acute neurogenic vasospasm.
Sydney Patrick Hall-Smith
Authors: R. Hall-Smith
Journal: BMJ (2002)

Former consultant dermatologist Brighton Health Authority and Hastings and Mid Sussex hospital groups (b 1919; q Edinburgh 1942; MD, FRCP Ed, FRCP), d 26 January 2002.

He served in the Royal Army Medical Corps in France, the Middle East, and Cyprus. Following demobilisation in 1947 he became senior registrar at the London Hospital and was appointed consultant dermatologist for two sessions in Brighton in 1951. Further sessions in Hastings and Mid Sussex followed and between 1953 and 1970 Patrick described himself as a “dermatological commercial traveller” commuting between hospitals. In 1970 reorganisation led to a full time appointment in Brighton. Patrick was the co-author of Dermatology: Current Concepts and Practice, which ran to three editions. Predeceased by his wife, Angela, he leaves four children and seven grandchildren.
Polymorphisms of the Beta Chain of the High-Affinity Immunoglobulin E Receptor (Fc ɛ RI- β ) in South African Black and White Asthmatic and Nonasthmatic Individuals
Authors: SAMANTHA L. GREEN, M. CHRISTINE GAILLARD, ERNEST SONG, JOHN B. DEWAR, ANDREW HALKAS
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

We used amplification refractory mutation system–polymerase chain reaction (ARMS-PCR) to document the prevalence of three mutations in the beta chain of the high-affinity IgE receptor (Fc ɛ RI- β ): I181L, V183L, and E237G in a sample of black and white asthmatic and control subjects in South Africa to determine whether these variants contribute to the enhanced IgE responses in these groups and also to determine whether the discrepancy in the prevalence of atopy in these groups could be attributed to these variants, as whites tend to be more atopic than blacks. There was a significant difference in the frequency of I181L between white asthmatics (28%) and white control subjects (3%) (p = 0.00001), and between black control subjects (16%) and white control subjects (p = 0.002); no difference in the frequency of I181L was observed between black asthmatics (22%) and black control subjects (16%). V183L was found in one black asthmatic who was also positive for I181L and E237G. There was a significant difference in the frequency of E237G between black asthmatics (20%) and white asthmatics (12%) (p = 0.05), and between control subjects (20%) and white control subjects (5%) (p = 0.003). E237G was more prevalent in blacks (20%) than in whites (8.5%) (p = 0.001). I181L might predispose to atopy in the white population, but not in the black population. The significantly higher prevalence of E237G in blacks than in whites might explain why blacks tend to have more severe asthma than whites and might offer more insight into the higher asthma mortality rate in the black population as compared with the white population.
Mitochondrial Biogenesis Is Impaired in Osteoarthritis Chondrocytes but Reversible via Peroxisome Proliferator–Activated Receptor γ Coactivator 1α
Authors: Yun Wang, Xianling Zhao, Martin Lotz, Robert Terkeltaub, Ru Liu‐Bryan
Journal: Arthritis & Rheumatology (2015)

The etiology of chondrocyte mitochondrial dysfunction in osteoarthritis (OA) is not completely understood. OA chondrocytes are deficient in the metabolic biosensors active AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT-1), which modulate the mitochondrial biogenesis "master regulator" peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). Moreover, PGC-1α critically mediates AMPK anticatabolic activity in chondrocytes. The aim of this study was to test the hypothesis that mitochondrial biogenesis is deficient in human OA chondrocytes and that this deficiency functionally increases chondrocyte procatabolic responses, which are reversed by activation of the AMPK/SIRT-1/PGC-1α pathway.We assessed the expression and activity (phosphorylation) of AMPKα, SIRT-1, and PGC-1α in human knee chondrocytes and human and mouse knee cartilage, and we defined and compared the content and function of mitochondria, including oxidative phosphorylation and expression of mitochondrial biogenesis factors (mitochondrial transcriptional factor A [TFAM] and nuclear respiratory factors [NRFs]).Human knee OA chondrocytes had a decreased mitochondrial biogenesis capacity, which was linked to reduced AMPKα activity and decreased expression of SIRT-1, PGC-1α, TFAM, NRF-1, and NRF-2. Human knee OA and aging mouse knee cartilage had decreased expression of TFAM and ubiquinol-cytochrome c reductase core protein, a subunit of mitochondrial complex III, in situ. Chondrocyte TFAM knockdown inhibited mitochondrial biogenesis and enhanced procatabolic responses to interleukin-1β. Finally, activation of AMPK by A-769662 increased PGC-1α expression via SIRT-1 and reversed impairments in mitochondrial biogenesis, oxidative phosphorylation, and intracellular ATP in human knee OA chondrocytes.Mitochondrial biogenesis is deficient in human OA chondrocytes, and this deficiency promotes chondrocyte procatabolic responses. TFAM-mediated activation of the AMPK/SIRT-1/PGC-1α pathway reverses these effects, suggesting translational potential of pharmacologic AMPK activators to limit OA progression.
The end-effectors of preconditioning protection against myocardial cell death secondary to ischemia–reperfusion
Authors: D GARCIADORADO, A RODRIGUEZSINOVAS, M RUIZMEANA, J INSERTE, L AGULLO, A CABESTRERO
Journal: Cardiovascular Research (2006)

Our understanding of the end-effectors involved in preconditioning protection is still very limited. This is partially due to an incomplete knowledge of the mechanisms responsible for acute sarcolemmal rupture and cell death during the first minutes of reperfusion, including the relative roles of hypercontracture-mediated sarcolemmal rupture and mitochondrial permeability transition pore (MPTP) opening-mediated cell death. In the present article, the role of proposed end-effectors of preconditioning protection, defined as molecules directly involved in cell death that are modified by ischemic preconditioning (IP), is examined. IP attenuates hypercontracture-mediated cell death, probably through several mechanisms, including attenuated calpain activation during reperfusion leading to preserved cytoskeletal integrity and accelerated recovery of Na+/K+-ATPase function, but probably also protein kinase G (PKG)-mediated improved calcium handling. The potential role of gap junctions in preconditioning protection is controversial, but the recently discovered mitochondrial localisation of connexin43 seems to play an important role in protection that has not yet been completely defined. Several recent studies suggest that IP can reduce MPTP opening during reperfusion and limit infarct size through this mechanism, although the contribution of this widely accepted mechanism to the infarct size reduction induced by IP in the intact heart needs to be established.
Detection of submucosal gastric fundal varices with multi-detector row CT angiography
Authors: J K Willmann, D Weishaupt, T Böhm, T Pfammatter, Burkhardt Seifert, B Marincek, P Bauerfeind
Journal: Gut (2003)

<b>Background and aim:</b> The diagnosis of submucosal fundal varices is challenging. Currently, endoscopy and endoscopic ultrasound (EUS) are considered most useful for this purpose. The aim of this study was to evaluate if multi-detector row CT (MDCT) angiography contributes to the diagnosis of submucosal fundal varices. <b>Patients and methods:</b> Twenty two patients with endoscopically suspected fundal varices were prospectively included in the study. All patients underwent EUS and MDCT angiography. Levels of agreement between EUS and MDCT angiography for the detection of submucosal and perigastric fundal varices were evaluated by three blinded independent readers. In addition, variceal size and location, as well as afferent and efferent vessels of the submucosal varices, were determined. <b>Results:</b> Good or excellent image quality of MDCT angiography was obtained in 21/22 patients (95%). Based on EUS, submucosal varices were detected in 16 of 22 patients (73%) and perigastric varices in 22/22 patients (100%). Using MDCT angiography, the presence of submucosal varices was confirmed in all of these 16 patients by all three readers. Perigastric varices were also confirmed in all 22 patients by all three readers. In addition, all three readers noted the presence of a submucosal varix in an additional patient which was not detected on initial EUS. MDCT angiography showed an excellent interobserver reliability with regard to variceal diameter (κ=0.90) and variceal location (κ=0.94). Based on MDCT angiography, afferent and efferent vessels of submucosal varices included the left gastric vein in 11 (65%), the posterior/short gastric veins in 15 (88%), gastrorenal shunts in 10 (59%), the left inferior phrenic vein in six (35%), and the left pericardiophrenic vein in six (35%) of 17 patients. <b>Conclusions:</b> MDCT angiography is equivalent to EUS in terms of detection and characterisation of fundal varices, in particular with regard to the distinction between submucosal and perigastric fundal varices.
Loss of RhoB Expression Promotes Migration and Invasion of Human Bronchial Cells Via Activation of AKT1
Authors: Emilie Bousquet, Julien Mazières, Maud Privat, Virginie Rizzati, Anne Casanova, Adeline Ledoux, Eliane Mery, Bettina Couderc, Gilles Favre, Anne Pradines
Journal: Cancer Research (2009)

Lung cancer is the leading cause of cancer-related death worldwide, mainly due to its highly metastatic properties. Previously, we reported an inverse correlation between RhoB expression and the progression of the lung cancer, occurring between preinvasive and invasive tumors. Herein, we mimicked the loss of RhoB observed throughout lung oncogenesis with RNA interference in nontumoral bronchial cell lines and analyzed the consequences on both cell transformation and invasion. Down-regulation of RhoB did not modify the cell growth properties but did promote migration and invasiveness. Furthermore, RhoB depletion was accompanied by modifications of actin and cell adhesion. The specific activation of the Akt1 isoform and Rac1 was found to be critical for this RhoB-mediated regulation of migration. Lastly, we showed that RhoB down-regulation consecutive to K-RasV12 cell transformation is critical for cell motility but not for cell proliferation. We propose that RhoB loss during lung cancer progression relates to the acquisition of invasiveness mediated by the phosphatidylinositol 3-kinase (PI3K)/AKT and Rac1 pathways rather than to tumor initiation.
Evidence against a Role for SV40 in Human Mesothelioma
Authors: James J. Manfredi, Jianli Dong, Wen-jun Liu, Lois Resnick-Silverman, Rui Qiao, Philippe Chahinian, Marko Saric, Allen R. Gibbs, James I. Phillips, J. Murray, Charles W. Axten, Robert P. Nolan, Stuart A. Aaronson
Journal: Cancer Research (2005)

Abstract SV40 has been implicated in the etiology of 40% to 60% of human mesotheliomas. These studies could have important medical implications concerning possible sources of human infection and potential therapies if human tumors are induced by this agent. We did PCR-based analysis to detect SV40 large T antigen DNA in human mesotheliomas. None of 69 tumors in which a single copy gene was readily amplified contained detectable SV40 large T antigen sequences. Under these conditions, it was possible to detect one copy of integrated SV40 DNA per cell in a mixture containing a 5,000-fold excess of normal cells using formalin-fixed preparations. Kidney, a known reservoir of SV40 in monkeys, from some of these individuals were also negative for SV40 large T antigen sequences. A subset of mesotheliomas was analyzed for SV40 large T antigen expression by immunostaining with a highly specific SV40 antibody. These tumors as well as several human mesothelioma cell lines previously reported to contain SV40 large T antigen were negative for detection of the virally encoded oncoprotein. Moreover, mesothelioma cell lines with wild-type p53 showed normal p53 function in response to genotoxic stress, findings inconsistent with p53 inactivation by the putative presence of SV40 large T antigen. Taken together, these findings strongly argue against a role of SV40 by any known transformation mechanism in the etiology of the majority of human malignant mesotheliomas.
Measurement of intracellular mediators in enterocytes isolated from jejunal biopsy specimens of control and cystic fibrosis patients.
Authors: B W Hitchin, P R Dobson, B L Brown, J Hardcastle, P T Hardcastle, C J Taylor
Journal: Gut (1991)

A method that maximises the yield of viable enterocytes has been developed for the isolation of enterocytes from human jejunal biopsy specimens. These enterocytes have been used to study the values of intracellular free calcium and the rises in adenosine 3959-cyclic monophosphate (cAMP) induced by secretagogues in normal and cystic fibrosis cells. Basal intracellular free calcium of cystic fibrosis enterocytes, measured fluorimetrically with fura-2, was within the range of the basal intracellular free calcium of non-cystic fibrosis enterocytes (cystic fibrosis 263 nmol/l; non-cystic fibrosis 287 nmol/l). Changes in intracellular free calcium were observed after exposure to ionomycin: a 100 nmol/l solution induced a 2.5 fold increase in intracellular free calcium in the cystic fibrosis enterocytes and a 2.2 fold increase in the intracellular free calcium concentration of the non-cystic fibrosis enterocytes. Basal cAMP values were not significantly different between cystic fibrosis and non-cystic fibrosis enterocytes (cystic fibrosis 575 fmol/100,000 cells; non-cystic fibrosis 716 fmol/100,000 cells, p greater than 0.05) and the enterocyte cAMP value increased in response to stimulation with prostaglandin E2 (7 mumol/l) (cystic fibrosis 2.2 fold increase over basal, p less than 0.05; non-cystic fibrosis 1.9 fold stimulation over basal, p less than 0.05) and vasoactive intestinal polypeptide (100 nmol/l) (cystic fibrosis 7.1 fold increase over basal, p less than 0.05; non-cystic fibrosis 5.8 fold increase over basal, p less than 0.05). There was no significant difference in the magnitude of the response between cystic fibrosis and non-cystic fibrosis enterocytes (p greater than 0.05). These results indicate that the cystic fibrosis defect in the small intestine, as in other affected epithelia, seems to be distal to the production of second messengers. The small intestine is therefore an appropriate model in which to study the biochemical defect in cystic fibrosis.