tbuckley/cabot-search huggingface dataset:
Drug-induced apoptosis in hepatoma cells is mediated by the CD95 (APO-1/Fas) receptor/ligand system and involves activation of wild-type p53.
Authors: M Müller, S Strand, H Hug, E M Heinemann, H Walczak, W J Hofmann, W Stremmel, P H Krammer, P R Galle
Journal: Journal of Clinical Investigation (1997)

Chemotherapeutic drugs are cytotoxic by induction of apoptosis in drug-sensitive cells. We investigated the mechanism of bleomycin-induced cytotoxicity in hepatoma cells. At concentrations present in the sera of patients during therapy, bleomycin induced transient accumulation of nuclear wild-type (wt) p53 and upregulated expression of cell surface CD95 (APO-1/Fas) receptor in hepatoma cells carrying wt p53 (HepG2). Bleomycin did not increase CD95 in hepatoma cells with mutated p53 (Huh7) or in hepatoma cells which were p53-/- (Hep3B). In addition, sensitivity towards CD95-mediated apoptosis was also increased in wt p53 positive HepG2 cells. Microinjection of wt p53 cDNA into HepG2 cells had the same effect. In contrast, bleomycin did not enhance susceptibility towards CD95-mediated apoptosis in Huh7 and in Hep3B cells. Furthermore, bleomycin treatment of HepG2 cells increased CD95 ligand (CD95L) mRNA expression. Most notably, bleomycin-induced apoptosis in HepG2 cells was almost completely inhibited by antibodies which interfere with CD95 receptor/ligand interaction. These data suggest that apoptosis induced by bleomycin is mediated, at least in part, by p53-dependent stimulation of the CD95 receptor/ligand system. The same applies to other anti-cancer drugs such as cisplatin and methotrexate. These data may have major consequences for drug treatment of cancer and the explanation of drug sensitivity and resistance.
Histone acetylation and histone deacetylase activity of magnesium valproate in tumor and peripheral blood of patients with cervical cancer. A phase I study
Authors: Alma Chavez-Blanco, Blanca Segura-Pacheco, Enrique Perez-Cardenas, Lucia Taja-Chayeb, Lucely Cetina, Myrna Candelaria, David Cantu, Aurora Gonzalez-Fierro, Patricia Garcia-Lopez, Pilar Zambrano, Carlos Perez-Plasencia, Gustavo Cabrera, Catalina Trejo-Becerril, Enrique Angeles, Alfonso Duenas-Gonzalez
Journal: Molecular Cancer (2005)

Abstract Background The development of cancer has been associated with epigenetic alterations such as aberrant histone deacetylase (HDAC) activity. It was recently reported that valproic acid is an effective inhibitor of histone deacetylases and as such induces tumor cell differentiation, apoptosis, or growth arrest. Methods Twelve newly diagnosed patients with cervical cancer were treated with magnesium valproate after a baseline tumor biopsy and blood sampling at the following dose levels (four patients each): 20 mg/kg; 30 mg/kg, or 40 mg/kg for 5 days via oral route. At day 6, tumor and blood sampling were repeated and the study protocol ended. Tumor acetylation of H3 and H4 histones and HDAC activity were evaluated by Western blot and colorimetric HDAC assay respectively. Blood levels of valproic acid were determined at day 6 once the steady-state was reached. Toxicity of treatment was evaluated at the end of study period. Results All patients completed the study medication. Mean daily dose for all patients was 1,890 mg. Corresponding means for the doses 20-, 30-, and 40-mg/kg were 1245, 2000, and 2425 mg, respectively. Depressed level of consciousness grade 2 was registered in nine patients. Ten patients were evaluated for H3 and H4 acetylation and HDAC activity. After treatment, we observed hyperacetylation of H3 and H4 in the tumors of nine and seven patients, respectively, whereas six patients demonstrated hyperacetylation of both histones. Serum levels of valproic acid ranged from 73.6–170.49 μg/mL. Tumor deacetylase activity decreased in eight patients (80%), whereas two had either no change or a mild increase. There was a statistically significant difference between pre and post-treatment values of HDAC activity (mean, 0.36 vs. 0.21, two-tailed t test p &lt; 0.0264). There was no correlation between H3 and H4 tumor hyperacetylation with serum levels of valproic acid. Conclusion Magnesium valproate at a dose between 20 and 40 mg/kg inhibits deacetylase activity and hyperacetylates histones in tumor tissues.
Respiratory syncytial virus therapy and prophylaxis: have we finally turned the corner?
Authors: R. G. Hegele
Journal: European Respiratory Journal (2011)

It is a grim reality that the text comprising introductory paragraphs to articles about respiratory syncytial virus (RSV) has changed very little over the years, the leitmotif being that RSV is a major cause of serious respiratory illnesses such as bronchiolitis and pneumonia worldwide, yet no safe, effective vaccine or good antiviral therapy is available. In this issue of the European Respiratory Journal , Olszewska et al. [1] report an exciting advance that could well be a key step toward pulling the field of anti-RSV interventions out of its doldrums. TMC353121, a remarkable “designer” molecule with a rather unremarkable name, is a potent pharmacological inhibitor of the RSV fusion (F) protein, a viral protein crucial to initial entry of RSV into cells and in subsequent cell-to-cell spread of infection. In contrast to many other F inhibitors that have been developed as promising pharmaceuticals and then abandoned, Olszewska et al. [1] used a mouse model to provide compelling evidence that TMC353121 can be used either prophylactically or therapeutically to decrease RSV lung infection and virus-associated lung inflammation and histopathology. This work extends the previous success of palivizumab (Synagis®; MedImmune, Gaithersburg, MD, USA), a humanised monoclonal antibody directed against the RSV F protein, an effective prophylactic that is used in children considered at high risk for serious RSV infections [2]. TMC353121 appears to have a suitable pharmacokinetic and safety profile and is amenable to a variety of dosing regimens. Importantly, and if TMC353121 administration is started within 48 h of RSV infection, the drug is an effective therapeutic agent. The 48-h time window between onset of infection and onset of treatment has bona fide …
PI3K signaling of autophagy is required for starvation tolerance and virulenceof Cryptococcus neoformans
Authors: Guowu Hu, Moshe Hacham, Scott R. Waterman, John Panepinto, Soowan Shin, Xiaoguang Liu, Jack Gibbons, Tibor Valyi-Nagy, Keisuke Obara, H. Ari Jaffe, Yoshinori Ohsumi, Peter R. Williamson
Journal: Journal of Clinical Investigation (2008)

Autophagy is a process by which cells recycle cytoplasm and defective organelles during stress situations such as nutrient starvation. It can also be used by host cells as an immune defense mechanism to eliminate infectious pathogens. Here we describe the use of autophagy as a survival mechanism and virulence-associated trait by the human fungal pathogen Cryptococcus neoformans. We report that a mutant form of C. neoformans lacking the Vps34 PI3K (vps34Delta), which is known to be involved in autophagy in ascomycete yeast, was defective in the formation of autophagy-related 8-labeled (Atg8-labeled) vesicles and showed a dramatic attenuation in virulence in mouse models of infection. In addition, autophagic vesicles were observed in WT but not vps34Delta cells after phagocytosis by a murine macrophage cell line, and Atg8 expression was exhibited in WT C. neoformans during human infection of brain. To dissect the contribution of defective autophagy in vps34Delta C. neoformans during pathogenesis, a strain of C. neoformans in which Atg8 expression was knocked down by RNA interference was constructed and these fungi also demonstrated markedly attenuated virulence in a mouse model of infection. These results demonstrated PI3K signaling and autophagy as a virulence-associated trait and survival mechanism during infection with a fungal pathogen. Moreover, the data show that molecular dissection of such pathogen stress-response pathways may identify new approaches for chemotherapeutic interventions.
Evaluation of differential disaccharide excretion in urine for non-invasive investigation of altered intestinal disaccharidase activity caused by alpha-glucosidase inhibition, primary hypolactasia, and coeliac disease.
Authors: I Bjarnason, R Batt, S Catt, A Macpherson, D Maxton, I S Menzies
Journal: Gut (1996)

The reliability of a quantitative method for the non-invasive assessment of intestinal disaccharide hydrolysis was assessed.Differential excretion of intact disaccharide, expressed as ratios of lactulose to appropriate hydrolysable disaccharides in urine collected following combined ingestion, has been investigated in healthy volunteers with drug induced alpha-glucosidase inhibition, in subjects with primary hypolactasia, and patients with coeliac disease.Oral administration of the alpha-glucosidase inhibitor 'Acarbose' (BAY g 5421, 200 mg) together with sucrose and lactulose increased the urinary sucrose/lactulose excretion ratios (% dose/10 h) fivefold. The effect was quantitatively reproducible, a higher dose of 'Acarbose' (500 mg) increasing the excretion ratio to about 1.0 indicating complete inhibition of intestinal sucrase activity. The suitability of the method for measuring differences in dose/response and duration of action was assessed by comparing three different alpha-glucosidase inhibitors (BAY g 5421, BAY m 1099, and BAY o 1248) and found to be satisfactory. Subjects with primary adult hypolactasia had urine lactose/lactulose excretion ratios raised to values indicating reduced rather than complete absence of lactase activity whereas sucrose/lactulose ratios were not significantly affected. 'Whole' intestinal disaccharidase activity assessed by this method demonstrated impairment of lactase, sucrase, and isomaltase in eight, one, and seven, respectively, of 20 patients with coeliac disease. By contrast in vitro assay of jejunal biopsy tissue indicated pan-disaccharidase deficiency in all but five of these patients. This shows the importance of distinguishing between 'local' and 'whole' intestinal performance.Differential urinary excretion of ingested disaccharides provides a reliable, quantitative, and non-invasive technique for assessing profiles of intestinal disaccharidase activity.
The Germinal Center/Activated B-Cell Subclassification Has a Prognostic Impact for Response to Salvage Therapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: A Bio-CORAL Study
Authors: Catherine Thieblemont, Josette Briere, Nicolas Mounier, Hans-Ullrich Voelker, Wendy Cuccuini, Edouard Hirchaud, Andreas Rosenwald, Andrew Jack, Christer Sundstrom, Sergio Cogliatti, Philippe Trougouboff, Ludmila Boudova, Loic Ysebaert, Jean Soulier, Catherine Chevalier, Dominique Bron, Norbert Schmitz, Philippe Gaulard, Remi Houlgatte, Christian Gisselbrecht
Journal: Journal of Clinical Oncology (2011)

Purpose To evaluate the prognostic value of the cell of origin (COO) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBLC), prospectively treated by rituximab, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP) versus rituximab, ifosfamide, carboplatin, and etoposide and followed by intensive therapy plus autologous stem-cell transplantation on the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) trial. Patients and Methods Among the 396 patients included on the trial, histologic material was available for a total of 249 patients at diagnosis (n = 189 patients) and/or at relapse (n = 147 patients), which included 87 matched pairs. The patient data were analyzed by immunochemistry for CD10, BCL6, MUM1, FOXP1, and BCL2 expression and by fluorescent in situ hybridization for BCL2, BCL6 and c-MYC breakpoints. The correlation with survival data was performed by using the log-rank test and the Cox model. Results Characteristics of immunophenotype and chromosomal abnormalities were statistically highly concordant in the matched biopsies. In univariate analysis, the presence of c-MYC gene rearrangement was the only parameter to be significantly correlated with a worse progression-free survival (PFS; P = .02) and a worse overall survival (P = .04). When treatment interaction was tested, the germinal center B (GCB) –like DLBCL that was based on the algorithm by Hans was significantly associated with a better PFS in the R-DHAP arm. In multivariate analysis, independent prognostic relevance was found for the GCB/non-GCB the Hans phenotype interaction treatment (P = .04), prior rituximab exposure (P = .0052), secondary age-adjusted International Prognostic Index (P = .039), and FoxP1 expression (P = .047). Confirmation was obtained by gene expression profiling in a subset of 39 patients. Conclusion COO remains a major and independent factor in relapsed/refractory DLBCL, with a better response to R-DHAP in GCB-like DLBCL. This needs confirmation by a prospective study.
Altered myocardial mechanics in diabetic rats.
Authors: F S Fein, L B Kornstein, J E Strobeck, J M Capasso, E H Sonnenblick
Journal: Circulation Research (1980)

Diabetes mellitus is associated frequently with congestive heart failure in humans, even in the absence of associated coronary disease or hypertension. Nevertheless, the effects of the diabetic state on myocardial mechanics have not been studied. Accordingly, diabetes was induced in female Wistar rats by injection of streptozotocin (60 mg/kg). Left ventricular papillary muscles were studied 5, 10, and 30 weeks later and compared with controls. Relaxation was delayed significantly and velocity of shortening was depressed at all loads. However, the passive and active force-length curves, as well as the series elastic properties, were not altered. The changes in cardiac performance were found over a range of muscle lengths, stimulus frequencies, and bath concentrations of calcium, glucose, and norepinephrine. The duration of diabetes had no major effect on the mechanical changes observed. The possible influences of drug-induced cardiac toxicity, malnutrition, and altered thyroid hormone levels have been considered; the latter two factors could not be excluded completely from having some influence on the mechanical properties of diabetic cardiac muscle. Evidence is cited showing abnormalities in calcium uptake by sarcoplasmic reticulum and depressed actomyosin ATPase activity. Thus a cardiomyopathic state has been produced in the rat consequent to the induction of experimental diabetes mellitus. Various mechanisms for this entity have been suggested.
Exercise capacity in a 78 year old patient with McArdle’s disease: it is never too late to start exercising
Authors: M Perez, M A Martin, J C Rubio, J L Maté-Muñoz, F Gómez-Gallego, C Foster, A L Andreu, J Arenas, A Lucia
Journal: British Journal of Sports Medicine (2006)

The case is reported of a 78 year old man with McArdle’s disease and a history of treated coronary heart disease. Despite the pre-exercise administration of sucrose allowing the patient to exercise with normal physiological responses, and without typical McArdle’s symptoms or biochemical evidence of muscle damage, his exercise capacity was very low (V̇ o 2 peak = 10.7 ml/min/kg), probably attributable to his lifetime of sedentary living. The data suggest that, with pre-exercise sucrose administration, such patients may be candidates for systematic reconditioning, which may improve functional capacity and quality of life.
Auditory Hair Cells: Structure, Function, Development, and Regeneration
Authors: J T Corwin, M E Warchol
Journal: Annual Review of Neuroscience (1991)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
Alteration of Ventricular Fibrillation by Flecainide, Verapamil, and Sotalol
Authors: Francisco J. Chorro, Joaquín Cánoves, Juan Guerrero, Luis Mainar, Juan Sanchis, Luis Such, Vicente López-Merino
Journal: Circulation (2000)

Background —The purpose of this study was to determine whether the myocardial electrophysiological properties are useful for predicting changes in the ventricular fibrillatory pattern. Methods and Results —Thirty-two Langendorff-perfused rabbit hearts were used to record ventricular fibrillatory activity with an epicardial multiple electrode. Under control conditions and after flecainide, verapamil, or d,l -sotalol, the dominant frequency (FrD), type of activation maps, conduction velocity, functional refractory period, and wavelength (WL) of excitation were determined during ventricular fibrillation (VF). Flecainide (1.9±0.3 versus 2.4±0.6 cm, P &lt;0.05) and sotalol (2.1±0.3 versus 2.5±0.5 cm, P &lt;0.05) prolonged WL and diminished FrD during VF, whereas verapamil (2.0±0.2 versus 1.7±0.2 cm, P &lt;0.001) shortened WL and increased FrD. Simple linear regression revealed an inverse relation between FrD and the functional refractory period ( r =0.66, P &lt;0.0001), a direct relation with respect to conduction velocity ( r =0.33, P &lt;0.01), and an inverse relation with respect to WL estimated during VF ( r =0.49, P &lt;0.0001). By stepwise multiple regression, the functional refractory periods were the only predictors of FrD. Flecainide and sotalol increased the circuit size of the reentrant activations, whereas verapamil decreased it. The 3 drugs significantly reduced the percentages of more complex activation maps during VF. Conclusions —The activation frequency is inversely related to WL during VF, although a closer relation is observed with the functional refractory period. Despite the diverging effects of verapamil versus flecainide and sotalol on the activation frequency, WL, and size of the reentrant circuits, all 3 drugs reduce activation pattern complexity during VF.
A biochemical study of hydroxyapatite crystal induced enzyme release from neutrophils.
Authors: J G Elferink, M Deierkauf
Journal: Annals of the Rheumatic Diseases (1987)

Addition of hydroxyapatite (HyAp) microcrystals to human neutrophils results in exocytosis of specific granules, measured as lysozyme release, and plasma membrane damage, evident from lactate dehydrogenase (LDH) release. The strong hydrogen acceptor polyvinylpyridine-N-oxide has no effect on enzyme release, but polyanions and negatively charged proteins such as albumin strongly inhibit HyAp induced enzyme release. HyAp crystals cause only slightly less membrane damage in neutrophil cytoplasts than in intact neutrophils. Removal of sialic acid from the cells did not affect HyAp induced enzyme release. Glucose, trapped in negatively charged liposomes, is released by HyAp crystals, whereas the crystals do not release glucose from positively charged liposomes. The results indicate that positive charges located on the HyAp crystals are of predominant importance for the effect of the crystals, and that the lipid part of the membrane might play an important part in the interaction.
Graft-Versus-Host Disease and Graft-Versus-Tumor Effects After Allogeneic Hematopoietic Cell Transplantation
Authors: Rainer Storb, Boglarka Gyurkocza, Barry E. Storer, Mohamed L. Sorror, Karl Blume, Dietger Niederwieser, Thomas R. Chauncey, Michael A. Pulsipher, Finn B. Petersen, Firoozeh Sahebi, Edward D. Agura, Parameswaran Hari, Benedetto Bruno, Peter A. McSweeney, Michael B. Maris, Richard T. Maziarz, Amelia A. Langston, Wolfgang Bethge, Lars Vindeløv, Georg-Nikolaus Franke, Ginna G. Laport, Andrew M. Yeager, Kai Hübel, H. Joachim Deeg, George E. Georges, Mary E.D. Flowers, Paul J. Martin, Marco Mielcarek, Ann E. Woolfrey, David G. Maloney, Brenda M. Sandmaier
Journal: Journal of Clinical Oncology (2013)

We designed a minimal-intensity conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) in patients with advanced hematologic malignancies unable to tolerate high-intensity regimens because of age, serious comorbidities, or previous high-dose HCT. The regimen allows the purest assessment of graft-versus-tumor (GVT) effects apart from conditioning and graft-versus-host disease (GVHD) not augmented by regimen-related toxicities.Patients received low-dose total-body irradiation ± fludarabine before HCT from HLA-matched related (n = 611) or unrelated (n = 481) donors, followed by mycophenolate mofetil and a calcineurin inhibitor to aid engraftment and control GVHD. Median patient age was 56 years (range, 7 to 75 years). Forty-five percent of patients had comorbidity scores of ≥ 3. Median follow-up time was 5 years (range, 0.6 to 12.7 years).Depending on disease risk, comorbidities, and GVHD, lasting remissions were seen in 45% to 75% of patients, and 5-year survival ranged from 25% to 60%. At 5 years, the nonrelapse mortality (NRM) rate was 24%, and the relapse mortality rate was 34.5%. Most NRM was a result of GVHD. The most significant factors associated with GVHD-associated NRM were serious comorbidities and grafts from unrelated donors. Most relapses occurred early while the immune system was compromised. GVT effects were comparable after unrelated and related grafts. Chronic GVHD, but not acute GVHD, further increased GVT effects. The potential benefit associated with chronic GVHD was outweighed by increased NRM.Allogeneic HCT relying on GVT effects is feasible and results in cures of an appreciable number of malignancies. Improved results could come from methods that control progression of malignancy early after HCT and effectively prevent GVHD.
Metabolic and Immunological Features of the Failing Islet-Transplanted Patient
Authors: Paolo Fiorina, Andrea Vergani, Alessandra Petrelli, Francesca D'Addio, Lucilla Monti, Reza Abdi, Emanuele Bosi, Paola Maffi, Antonio Secchi
Journal: Diabetes Care (2008)

This retrospective study was designed to identify metabolic and immune predictors of early islet allograft failure.We measured several metabolic and immunological markers at the time of pretransplant and several time points posttransplantation in 17 patients with long-term functioning graft (long fx) and 20 patients with short-term functioning graft (short fx).The short fx group showed higher insulin resistance, altered proinsulin processing, lower soluble interleukin-2 receptor (sIL-2r) (marker of T-cell activation), and higher soluble FasL (marker of apoptosis) during the entire follow-up, particularly at time of failure.Patients who experienced an early failure of islet allograft showed specific metabolic and immunological signs long before islet failure.
Residual proliferative cancer burden to predict long-term outcome following neoadjuvant chemotherapy
Authors: A. Sheri, I.E. Smith, S.R. Johnston, R. A'Hern, A. Nerurkar, R.L. Jones, M. Hills, S. Detre, S.E. Pinder, W.F. Symmans, M. Dowsett
Journal: Annals of Oncology (2014)

The purpose of this study was (i) to test the hypothesis that combining Ki67 with residual cancer burden (RCB) following neoadjuvant chemotherapy, as the residual proliferative cancer burden (RPCB), provides significantly more prognostic information than either alone; (ii) to determine whether also integrating information on ER and grade improves prognostic power.