tbuckley/cabot-search huggingface dataset:
GRP78/BiP Inhibits Endoplasmic Reticulum BIK and Protects Human Breast Cancer Cells against Estrogen Starvation–Induced Apoptosis
Authors: Yong Fu, Jianze Li, Amy S. Lee
Journal: Cancer Research (2007)

Abstract The recent development of hormonal therapy that blocks estrogen synthesis represents a major advance in the treatment of estrogen receptor–positive breast cancer. However, cancer cells often acquire adaptations resulting in resistance. A recent report reveals that estrogen starvation–induced apoptosis of breast cancer cells requires BIK, an apoptotic BH3-only protein located primarily at the endoplasmic reticulum (ER). Searching for novel partners that interact with BIK at the ER, we discovered that BIK selectively forms complex with the glucose-regulated protein GRP78/BiP, a major ER chaperone with prosurvival properties naturally induced in the tumor microenvironment. GRP78 overexpression decreases apoptosis of 293T cells induced by ER-targeted BIK. For estrogen-dependent MCF-7/BUS breast cancer cells, overexpression of GRP78 inhibits estrogen starvation–induced BAX activation, mitochondrial permeability transition, and consequent apoptosis. Further, knockdown of endogenous GRP78 by small interfering RNA (siRNA) sensitizes MCF-7/BUS cells to estrogen starvation–induced apoptosis. This effect was substantially reduced when the expression of BIK was also reduced by siRNA. Our results provide the first evidence that GRP78 confers resistance to estrogen starvation–induced apoptosis in human breast cancer cells via a novel mechanism mediated by BIK. These results further suggest that GRP78 expression level in the tumor cells may serve as a prognostic marker for responsiveness to hormonal therapy based on estrogen starvation and that combination therapy targeting GRP78 may enhance efficacy and reduce resistance. [Cancer Res 2007;67(8):3734–40]
Relative efficacy of human monocytes and dendritic cells as accessory cells for T cell replication.
Authors: W C Van Voorhis, J Valinsky, E Hoffman, J Luban, L S Hair, R M Steinman
Journal: The Journal of Experimental Medicine (1983)

Monocyte-specific monoclonal antibodies (7) were used to compare the efficacy of monocytes and dendritic cells as accessory or stimulator cells for human T cell replication. Both unfractionated and plastic-adherent mononuclear cells were first treated with a cytolytic antimonocyte antibody that kills greater than 95% of monocytes but not dendritic cells. When tested as stimulators of the mixed leukocyte reaction (MLR) and of oxidative mitogenesis (the proliferation of T cells modified with sodium periodate), the monocyte-depleted cells had normal or enhanced stimulatory capacity. Monocyte-depleted mononuclear cells also proliferated normally to soluble antigens (Candida albicans, tetanus toxoid), even under limiting conditions of cell dose, antigen dose, and culture time. Adherent blood mononuclear cells were next separated into monocyte-enriched and -depleted components using fluoresceinated antimonocyte antibody and the cell sorter. The depleted fraction (less than 2% monocytes by esterase staining and by cytology) contained the dendritic cells and exhibited at least 75% of the accessory activity. The monocyte-rich fraction (approximately 97% esterase positive) stimulated the MLR and oxidative mitogenesis weakly, and was comparable in potency to nonadherent cells. Cell-specific antibodies and complement were also used to prepare dendritic cells that were thoroughly depleted of monocytes and lymphocytes. The dendritic cells (70-80% pure) were potent stimulators of the allogeneic MLR, syngeneic MLR, and tetanus toxoid response, being active at stimulator to responder ratios of 1:100 or less. Taken together with previous studies (1, 2), these experiments indicate that the dendritic cell is the major stimulator of T cell replication in man. The contribution of class II products of the major histocompatibility complex (7) was then evaluated with a new monoclonal, 9.3F10. Accessory function was dramatically inhibited if cells bearing class II antigens were killed with 9.3F10 and complement, or if class II molecules were blocked by the addition of 9.3F10 Fab to the culture medium. The expression of 9.3F10 class II products was therefore studied on purified monocytes and dendritic cells. Most if not all cells in both populations reacted with 9.3F10, and each population exhibited approximately 150,000 125I-Fab 9.3F10 binding sites per cell. Since Ia+ dendritic cells are active accessory cells, but Ia+ monocytes are not, class II products are necessary but not sufficient for the stimulation of T cell proliferation in man.
Phylogenetic classification of Escherichia coli O157:H7 strains of human and bovine origin using a novel set of nucleotide polymorphisms
Authors: Michael L Clawson, James E Keen, Timothy PL Smith, Lisa M Durso, Tara G McDaneld, Robert E Mandrell, Margaret A Davis, James L Bono
Journal: Genome biology (2009)

Cattle are a reservoir of Shiga toxin-producing Escherichia coli O157:H7 (STEC O157), and are known to harbor subtypes not typically found in clinically ill humans. Consequently, nucleotide polymorphisms previously discovered via strains originating from human outbreaks may be restricted in their ability to distinguish STEC O157 genetic subtypes present in cattle. The objectives of this study were firstly to identify nucleotide polymorphisms in a diverse sampling of human and bovine STEC O157 strains, secondly to classify strains of either bovine or human origin by polymorphism-derived genotypes, and finally to compare the genotype diversity with pulsed-field gel electrophoresis (PFGE), a method currently used for assessing STEC O157 diversity.High-throughput 454 sequencing of pooled STEC O157 strain DNAs from human clinical cases (n = 91) and cattle (n = 102) identified 16,218 putative polymorphisms. From those, 178 were selected primarily within genomic regions conserved across E. coli serotypes and genotyped in 261 STEC O157 strains. Forty-two unique genotypes were observed that are tagged by a minimal set of 32 polymorphisms. Phylogenetic trees of the genotypes are divided into clades that represent strains of cattle origin, or cattle and human origin. Although PFGE diversity surpassed genotype diversity overall, ten PFGE patterns each occurred with multiple strains having different genotypes.Deep sequencing of pooled STEC O157 DNAs proved highly effective in polymorphism discovery. A polymorphism set has been identified that characterizes genetic diversity within STEC O157 strains of bovine origin, and a subset observed in human strains. The set may complement current techniques used to classify strains implicated in disease outbreaks.
Exercise physiology: people and ideas
Authors: T W Allen
Journal: British Journal of Sports Medicine (2005)

Edited by Charles M Tipton. Oxford University Press, 2003, £69.50, pp 510, hardcover. ISBN 0195125274

It is not often that one finds a systematic review of science history that reads like an exciting non-fiction novel, but Exercise physiology is just that. In fewer than 500 pages, a surprisingly in-depth story of the growth in the understanding of exercise physiology science is told. The authors trace the exciting journey of discovery—a journey that at times was painfully slow when centuries passed by in which no …
<i>KRAS</i> and <i>KIT</i> Gatekeeper Mutations Confer Polyclonal Primary Imatinib Resistance in GI Stromal Tumors: Relevance of Concomitant Phosphatidylinositol 3-Kinase/AKT Dysregulation
Authors: César Serrano, Yuexiang Wang, Adrián Mariño-Enríquez, Jen-Chieh Lee, Gloria Ravegnini, Jeffrey A. Morgan, Monica M. Bertagnolli, Carol Beadling, George D. Demetri, Christopher L. Corless, Michael C. Heinrich, Jonathan A. Fletcher
Journal: Journal of Clinical Oncology (2014)
Lymphocyte-Predominant Hodgkin’s Lymphoma in Children: Therapeutic Abstention After Initial Lymph Node Resection—A Study of the French Society of Pediatric Oncology
Authors: B. Pellegrino, M.J. Terrier-Lacombe, O. Oberlin, T. Leblanc, Y. Perel, Y. Bertrand, C. Beard, C. Edan, C. Schmitt, D. Plantaz, H. Pacquement, J.P. Vannier, C. Lambilliote, G. Couillault, A. Babin-Boilletot, I. Thuret, F. Demeocq, G. Leverger, G. Delsol, J. Landman-Parker
Journal: Journal of Clinical Oncology (2003)

To clarify treatment strategy for lymphocyte-predominant Hodgkin's lymphoma (LPHL), the French Society of Pediatric Oncology initiated a prospective, nonrandomized study in 1988. Patients received either standard treatment for Hodgkin's lymphoma or were not treated beyond initial adenectomy.From 1988 to 1998, 27 patients were available for study. Twenty-four patients were male, and median age was 10 years (range, 4 to 16 years). Twenty-two, two, and three patients had stage I, II, and III disease, respectively. Thirteen patients (stage I, n = 11; stage III, n = 2) received no further treatment after initial surgical adenectomy (SA). Fourteen patients received combined treatment (CT; n = 10), involved-field radiotherapy alone (n = 1), or chemotherapy alone (n = 3). The two groups were comparable for clinical status, treatment, and follow-up.Twenty-three of 27 patients achieved complete remission (CR). With a median follow-up time of 70 months (range, 32 to 214 months), overall survival to date is 100%, and overall event-free survival (EFS) is 69% +/- 10% (SA, 42% +/- 16%; CT, 90% +/- 8.6%; P <.04). If we considered only the patients in CR after initial surgery (n = 12), EFS was no longer significantly different between the two groups. Patients with residual mass after initial surgery (n = 15) had worse EFS if they did not receive complementary treatment (P <.05).Although based on a small number of patients, our study showed that (1). no further therapy is a valid therapeutic approach in LPHL patient in CR after initial lymph node resection, and (2). complementary treatment diminishes relapse frequency but has no impact on survival.
C-Abl Is Required for the Development of Hyperoxia-Induced Retinopathy
Authors: Irene Nunes, Rosemary D. Higgins, Lucia Zanetta, Peter Shamamian, Stephen P. Goff
Journal: The Journal of Experimental Medicine (2001)

The requirement for the nonreceptor tyrosine kinase c-abl in the pathogenesis of retinopathy of prematurity (ROP) was examined using the mouse model for ROP and c-abl–deficient mice. Hyperoxia-induced retinal neovascularization was observed in wild-type and heterozygous mice but animals that were homozygous null for c-abl did not develop a vasoproliferative retinopathy in response to hyperoxia. Two gene products, endothelin-1 (ET-1) and vascular endothelial growth factor (VEGF), have been implicated in the pathogenesis of ROP. The mRNA expression of ET-1 and VEGF was assessed in mice maintained in normoxia and in hyperoxia-exposed mice. ET-1 mRNA levels were unchanged in wild-type mice throughout the hyperoxia treatment, suggesting that ET-1 mRNA expression is not regulated by the increase in inspired oxygen. In wild-type mice maintained in room air, VEGF mRNA levels rose threefold from postnatal day 6 (P6) to P17. When wild-type mice were treated with the hyperoxia regimen, a fivefold decrease in VEGF mRNA expression was observed from P7 to P16. However, retinal VEGF expression in hyperoxia-treated homozygous null mice did not decrease and remained at control levels. These data suggest that c-abl is required for the hyperoxia-induced retinal neovascularization and hyperoxia-induced decrease in VEGF mRNA levels.
Persistent improved results after adding vincristine and bleomycin to a cyclophosphamide/hydroxorubicin/Vm-26/prednisone combination (CHVmP) in stage III-IV intermediate- and high-grade non-Hodgkin's lymphoma
Authors: J.H. Meerwaldt, P. Carde, R. Somers, J. Thomas, J.C. Kluin-Nelemans, D. Bron, E.M. Noordijk, J.M. Cosset, L. Bijnens, I. Teodorovic, A. Hagenbeek
Journal: Annals of Oncology (1997)
Serum Fucosylated Prostate-specific Antigen (PSA) Improves the Differentiation of Aggressive from Non-aggressive Prostate Cancers
Authors: Qing Kay Li, Li Chen, Ming-Hui Ao, Joyce Hanching Chiu, Zhen Zhang, Hui Zhang, Daniel W Chan
Journal: Theranostics (2015)

Clinically, it is still challenging to differentiate aggressive from non-aggressive prostate cancers (Pca) by non-invasive approaches. Our recent studies showed that overexpression of alpha (1-6) fucosyltransferase played an important role in Pca cells. In this study, we have investigated levels of glycoproteins and their fucosylated glycoforms in sera of Pca patients, as well as the potential utility of fucosylated glycoproteins in the identification of aggressive Pca.
Phase II Study of Troxacitabine, a Novel Dioxolane Nucleoside Analog, in Patients With Refractory Leukemia
Authors: F. J. Giles
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To investigate the activity of a novel dioxolane l-nucleoside analog, troxacitabine (l-(−)-OddC, BCH-4556), in patients with refractory leukemia. PATIENTS AND METHODS: Study participants were patients with refractory or relapsed acute myeloid (AML) or lymphocytic (ALL) leukemia, myelodysplastic syndromes (MDS), or chronic myelogenous leukemia in blastic phase (CML-BP). Troxacitabine was provided as an intravenous infusion for more than 30 minutes daily for 5 days at a dose of 8.0 mg/m2/d (40 mg/m2 per course). Courses were given every 3 to 4 weeks according to antileukemic efficacy. RESULTS: Forty-two patients (AML, 18 patients; MDS, one patient; ALL, six patients; CML-BP, 17 patients) were treated. Median age was 51 years (range, 23 to 80 years); 22 patients were male. Stomatitis was the most significant adverse event, with three patients (7%) and two patients (5%), respectively, experiencing grade 3 or 4 toxicity. Ten patients (24%) had grade 3 hand-foot syndrome, and two patients (5%) had grade 3 skin rash. One patient (2%) had grade 3 fatigue and anorexia. Marrow hypoplasia occurred between days 14 and 28 in 12 (75%) of 16 assessable patients with AML. Two complete remissions and one partial remission (18%) were observed in 16 assessable patients with AML. None of six patients with ALL responded. Six (37%) of 16 assessable patients with CML-BP experienced a return to chronic-phase disease. CONCLUSION: Troxacitabine has significant antileukemic activity in patients with AML and CML-BP.
Molecular Cloning of the cDNA Encoding pp36, a Tyrosine-phosphorylated Adaptor Protein Selectively Expressed by T Cells and Natural Killer Cells
Authors: John R. Weber, Sigurd Ørstavik, Knut Martin Torgersen, Niels Christian Danbolt, Siri F. Berg, James C. Ryan, Kjetil Taskén, John B. Imboden, John T. Vaage
Journal: The Journal of Experimental Medicine (1998)

Activation of T and natural killer (NK) cells leads to the tyrosine phosphorylation of pp36 and to its association with several signaling molecules, including phospholipase Cγ-1 and Grb2. Microsequencing of peptides derived from purified rat pp36 protein led to the cloning, in rat and man, of cDNA encoding a T- and NK cell–specific protein with several putative Src homology 2 domain–binding motifs. A rabbit antiserum directed against a peptide sequence from the cloned rat molecule recognized tyrosine phosphorylated pp36 from pervanadate-treated rat thymocytes. When expressed in 293T human fibroblast cells and tyrosine-phosphorylated, pp36 associated with phospholipase Cγ-1 and Grb2. Studies with GST–Grb2 fusion proteins demonstrated that the association was specific for the Src homology 2 domain of Grb-2. Molecular cloning of the gene encoding pp36 should facilitate studies examining the role of this adaptor protein in proximal signaling events during T and NK cell activation.
Preprocedural TIMI flow and mortality in patients with acute myocardial infarction treated by primary angioplasty
Authors: Giuseppe De Luca, Nicolette Ernst, Felix Zijlstra, Arnoud W.J. van't Hof, Jan C.A. Hoorntje, Jan-Henk E. Dambrink, A.T.Marcel Gosslink, Menko-Jan de Boer, Harry Suryapranata
Journal: Journal of the American College of Cardiology (2004)
The Development of Atypical Hemolytic Uremic Syndrome Depends on Complement C5
Authors: Elena Goicoechea de Jorge, Paolo Macor, Danielle Paixão-Cavalcante, Kirsten L. Rose, Franco Tedesco, H. Terence Cook, Marina Botto, Matthew C. Pickering
Journal: Journal of the American Society of Nephrology (2010)

Gene variants in the alternative pathway of the complement system strongly associate with atypical hemolytic uremic syndrome (aHUS), presumably by predisposing to increased complement activation within the kidney. Complement factor H (CFH) is the major regulator of complement activation through the alternative pathway. Factor H-deficient mice transgenically expressing a mutant CFH protein (Cfh(-/-).FHΔ16-20) that functionally mimics the CFH mutations reported in aHUS patients spontaneously develop thrombotic microangiopathy. To investigate the role of complement C5 activation in this aHUS model, we generated C5-deficient Cfh(-/-).FHΔ16-20 mice. Both C5-sufficient and C5-deficient Cfh(-/-).FHΔ16-20 mice had abnormal C3 deposition within the kidney, but spontaneous aHUS did not develop in any of the C5-deficient mice. Furthermore, although Cfh(-/-).FHΔ16-20 animals demonstrated marked hypersensitivity to experimentally triggered renal injury, animals with concomitant C5 deficiency did not. These data demonstrate a critical role for C5 activation in both spontaneous aHUS and experimentally triggered renal injury in animals with defective complement factor H function. This study provides a rationale to investigate therapeutic inhibition of C5 in human aHUS.
Borg scores before and after challenge with adenosine 5′-monophosphate and methacholine in subjects with COPD and asthma
Authors: S.R. Rutgers, N.H.T. ten Hacken, G.H Koeter, D.S Postma
Journal: European Respiratory Journal (2000)

Dyspnoea differs between subjects with chronic obstructive pulmonary disease (COPD) and asthma, partly because the underlying mechanisms for bronchoconstriction differ. This study investigated the possible role of inflammation and the contribution of clinical variables on dyspnoea in subjects with COPD and asthma. Forty-eight smoking subjects with COPD and 21 nonsmoking subjects with asthma, were challenged with adenosine 59-monophosphate (AMP) and methacholine. The Borg score was assessed before and after each challenge. Mean increases in Borg score (per percentage decrease in baseline forced expiratory volume in one second (FEV1)) were significantly smaller in COPD than in asthma (p&lt;0.01), values being 0.055 and 0.045 in COPD and 0.122 and 0.093 in asthma respectively. This difference was largely due to the fact that one-third of the subjects with COPD did not increase their Borg score during bronchoconstriction. The increase in Borg tended to be larger during AMP than during methacholine challenge, both in asthma and COPD. Changes in Borg scores were explained by age in COPD and by the Borg score before AMP challenge in asthma. The authors conclude that perception of dyspnoea during adenosine 59-monophosphate and methacholine induced bronchoconstriction is lower in chronic obstructive pulmonary disease than in asthma and that age contributes to this difference. As adenosine 59-monophosphate is regarded as an indirect marker of airway inflammation, the results suggest that inflammation is not important because both groups showed similar responses on such provocations.
Fungal Nail Disease
Authors: David de Berker
Journal: New England Journal of Medicine (2009)

A 68-year-old man reports changes in his left big toenail. It has been discolored distally for the past 2 years. It has become thickened and difficult to cut and is painful when the man is walking in certain shoes. He is otherwise well. On physical examination, the nail appears thickened, has crumbling yellow material beneath, and is more discolored distally than proximally. The nearby skin is normal, although the interdigital space of the little toe is macerated. How should his case be managed?
Human Cd25+Cd4+ T Regulatory Cells Suppress Naive and Memory T Cell Proliferation and Can Be Expanded in Vitro without Loss of Function
Authors: Megan K. Levings, Romina Sangregorio, Maria-Grazia Roncarolo
Journal: The Journal of Experimental Medicine (2001)

Active suppression by T regulatory (Tr) cells plays an important role in the downregulation of T cell responses to foreign and self-antigens. Mouse CD4(+) Tr cells that express CD25 possess remarkable suppressive activity in vitro and in autoimmune disease models in vivo. Thus far, the existence of a similar subset of CD25(+)CD4(+) Tr cells in humans has not been reported. Here we show that human CD25(+)CD4(+) Tr cells isolated from peripheral blood failed to proliferate and displayed reduced expression of CD40 ligand (CD40L), in response to T cell receptor-mediated polyclonal activation, but strongly upregulated cytotoxic T lymphocyte-associated antigen (CTLA)-4. Human CD25(+)CD4(+) Tr cells also did not proliferate in response to allogeneic antigen-presenting cells, but they produced interleukin (IL)-10, transforming growth factor (TGF)-beta, low levels of interferon (IFN)-gamma, and no IL-4 or IL-2. Importantly, CD25(+)CD4(+) Tr cells strongly inhibited the proliferative responses of both naive and memory CD4(+) T cells to alloantigens, but neither IL-10, TGF-beta, nor CTLA-4 seemed to be directly required for their suppressive effects. CD25(+)CD4(+) Tr cells could be expanded in vitro in the presence of IL-2 and allogeneic feeder cells and maintained their suppressive capacities. These findings that CD25(+)CD4(+) Tr cells with immunosuppressive effects can be isolated from peripheral blood and expanded in vitro without loss of function represent a major advance towards the therapeutic use of these cells in T cell-mediated diseases.
Influence of nasal obstruction on auto-CPAP behaviour during sleep in sleep apnoea/hypopnoea syndrome
Authors: C. Lafond, F. Series
Journal: Thorax (1998)

<h3>BACKGROUND</h3> Auto-CPAP machines have been developed to adapt automatically the positive pressure level to the required needs. The auto-CPAP response to transient nasal obstruction was tested during sleep in patients with sleep apnoea/hypopnoea syndrome (SAHS). <h3>METHODS</h3> Nasal obstruction was induced by local instillation of histamine. Fourteen nasal challenges were performed on eight patients, seven while the patients were on the “Morphée plus” apparatus and the other seven with the patients on the “Horizon” machine. <h3>RESULTS</h3> Nasal resistance increased initially by a mean (SD) of 166 (66)% during the trials with the “Morphée plus” and by 118 (44)% with the “Horizon” machine. The increase in nasal resistance was always accompanied by flow limitation with one exception. Mask pressure initially decreased to the minimal permitted value as nasal resistance increased with the “Morphée plus” device. A late increase of the positive pressure level occurred sometimes. Mask pressure did not change with increasing nasal resistance when the “Horizon” device was used. <h3>CONCLUSION</h3> Neither the “Morphée plus” nor the “Horizon” device abolished flow limited breaths and resulting sleep fragmentation. We conclude that, despite the different algorithm of pressure changes, these auto-CPAP machines do not adequately respond to an acute increase in nasal resistance.