tbuckley/cabot-search huggingface dataset:
Evidence for Class-Specific Factors in Immunoglobulin Isotype Switching
Authors: Ananth Shanmugam, Meng-Jiao Shi, Lauren Yauch, Janet Stavnezer, Amy L. Kenter
Journal: The Journal of Experimental Medicine (2000)

Immunoglobulin class switch recombination (SR) occurs by a B cell-specific, intrachromosomal deletional process between switch regions. We have developed a plasmid-based transient transfection assay for SR to test for the presence of transacting switch activities. The plasmids are novel in that they lack a eukaryotic origin of DNA replication. The recombination activity of these switch substrates is restricted to a subset of B cell lines that support isotype switching on their endogenous loci and to mitogen-activated normal splenic B cells. The factors required for extrachromosomal plasmid recombination are constitutively expressed in proliferating splenic B cells and in B cell lines capable of inducibly undergoing immunoglobulin SR on their chromosomal genes. These studies suggest that mitogens that induce switching on the chromosome induce accessibility rather than switch recombinase activity. Finally, we provide evidence for two distinct switching activities which independently mediate mu-->alpha and mu-->gamma3 SR.
Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial
Authors: Jeffrey S Weber, Sandra P D'Angelo, David Minor, F Stephen Hodi, Ralf Gutzmer, Bart Neyns, Christoph Hoeller, Nikhil I Khushalani, Wilson H Miller, Christopher D Lao, Gerald P Linette, Luc Thomas, Paul Lorigan, Kenneth F Grossmann, Jessica C Hassel, Michele Maio, Mario Sznol, Paolo A Ascierto, Peter Mohr, Bartosz Chmielowski, Alan Bryce, Inge M Svane, Jean-Jacques Grob, Angela M Krackhardt, Christine Horak, Alexandre Lambert, Arvin S Yang, James Larkin
Journal: The Lancet Oncology (2015)
Reduced Cardiovascular Morbidity and Mortality in Hypertensive Diabetic Patients on First-Line Therapy With an ACE Inhibitor Compared With a Diuretic/β-Blocker–Based Treatment Regimen
Authors: Leo Niskanen, Thomas Hedner, Lennart Hansson, Jan Lanke, Anders Niklason
Journal: Diabetes Care (2001)

OBJECTIVE—The Captopril Prevention Project (CAPPP) evaluated the effects of an ACE inhibitor–based therapeutic regimen on cardiovascular mortality and morbidity in hypertension. One planned subanalysis of the CAPPP was to evaluate the outcome in the diabetic patient group. RESEARCH DESIGN AND METHODS—In the CAPPP, 572 (4.9% of 10,985 hypertensive patients) had diabetes at baseline and were studied according to a prospective, randomized, open, blinded, end point trial design. Patients aged 25–66 years with diastolic blood pressure ≥100 mmHg were included and randomized to receive either captopril or conventional antihypertensive treatment (diuretics and/or β-blockers). RESULTS—The primary end point, fatal and nonfatal myocardial infarction and stroke as well as other cardiovascular deaths, was markedly lower in the captopril than in the conventional therapy group (relative risk [RR] = 0.59; P = 0.018). Specifically, cardiovascular mortality, defined as fatal stroke and myocardial infarction, sudden death, and other cardiovascular death, tended to be lower in the captopril group (RR = 0.48; P = 0.084), and no difference was observed between the study groups for stroke (RR = 1.02; P = 0.96). Myocardial infarctions were less frequent in the captopril group than in the conventional therapy group (RR = 0.34; P = 0.002). Furthermore, total mortality was lower in the captopril as compared with the conventional therapy group (RR = 0.54; P = 0.034). Patients with impaired metabolic control seemed to benefit the most from ACE inhibitor–based therapy. CONCLUSIONS—Captopril is superior to a diuretic/β-blocker antihypertensive treatment regimen in preventing cardiovascular events in hypertensive diabetic patients, especially in those with metabolic decompensation.
A Phase I and Pharmacokinetic Study of Paclitaxel Poliglumex (XYOTAX), Investigating Both 3-Weekly and 2-Weekly Schedules
Authors: Alan V. Boddy, E. Ruth Plummer, Radha Todd, Julieann Sludden, Melanie Griffin, Lesley Robson, James Cassidy, Donald Bissett, Alberto Bernareggi, Mark W. Verrill, A. Hilary Calvert
Journal: Clinical Cancer Research (2005)

Abstract Purpose: To determine the safety, maximum tolerated dose, pharmacokinetics, and toxicities associated with administration of paclitaxel poliglumex (PPX, XYOTAX, Cell Therapeutics, Inc., Bresso, Italy) given on either 3-weekly or 2-weekly schedule. Experimental Design: Nineteen patients were investigated on the 3-weekly phase Ia study and 11 patients on the 2-weekly phase Ib study. Dose escalation starting with 100% increments and one patient per dose level was modulated in accordance with the observed toxicities. Conjugated and unconjugated paclitaxel were measured in plasma. Results: Dose-limiting toxicity of neutropenia was encountered at 266 mg/m2 (paclitaxel equivalents) in phase Ia and the maximum tolerated dose was 233 mg/m2. Neuropathy was dose-limiting in phase Ib with a maximum tolerated dose of 177 mg/m2. Pharmacokinetic investigations indicated a prolonged half-life of &amp;gt;100 hours for conjugated taxanes. Plasma concentrations of unconjugated paclitaxel were similar to those following administration of an equivalent dose of Taxol. Two partial responses were observed, one in a patient with mesothelioma at 177 mg/m2 in phase Ia and one in a patient with gastric carcinoma at 175 mg/m2 in phase Ib. Conclusion: PPX is a water-soluble paclitaxel-polymer conjugate with a prolonged half-life and limited volume of distribution. Dose-limiting toxicities were neutropenia and neuropathy. PPX showed activity in this patient population.
Activating Fc γ receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies
Authors: Yannick Bulliard, Rose Jolicoeur, Maurice Windman, Sarah M. Rue, Seth Ettenberg, Deborah A. Knee, Nicholas S. Wilson, Glenn Dranoff, Jennifer L. Brogdon
Journal: The Journal of Experimental Medicine (2013)

Fc γ receptor (FcγR) coengagement can facilitate antibody-mediated receptor activation in target cells. In particular, agonistic antibodies that target tumor necrosis factor receptor (TNFR) family members have shown dependence on expression of the inhibitory FcγR, FcγRIIB. It remains unclear if engagement of FcγRIIB also extends to the activities of antibodies targeting immunoregulatory TNFRs expressed by T cells. We have explored the requirement for activating and inhibitory FcγRs for the antitumor effects of antibodies targeting the TNFR glucocorticoid-induced TNFR-related protein (GITR; TNFRSF18; CD357) expressed on activated and regulatory T cells (T reg cells). We found that although FcγRIIB was dispensable for the in vivo efficacy of anti-GITR antibodies, in contrast, activating FcγRs were essential. Surprisingly, the dependence on activating FcγRs extended to an antibody targeting the non-TNFR receptor CTLA-4 (CD152) that acts as a negative regulator of T cell immunity. We define a common mechanism that correlated with tumor efficacy, whereby antibodies that coengaged activating FcγRs expressed by tumor-associated leukocytes facilitated the selective elimination of intratumoral T cell populations, particularly T reg cells. These findings may have broad implications for antibody engineering efforts aimed at enhancing the therapeutic activity of immunomodulatory antibodies.
Aberrant ERK 1/2 complex activation and localization in scrapie-infected GT1-1 cells
Authors: Alessandro Didonna, Giuseppe Legname
Journal: Molecular Neurodegeneration (2010)

Fatal neurodegenerative disorders such as Creutzfeldt-Jakob and Gerstmann-Sträussler-Scheinker diseases in humans, scrapie and bovine spongiform encephalopathy in animals, are characterized by the accumulation in the brain of a pathological form of the prion protein (PrP) denominated PrPSc. The latter derives from the host cellular form, PrPC, through a process whereby portions of its alpha-helical and coil structures are refolded into beta-sheet structures.In this work, the widely known in vitro model of prion replication, hypothalamic GT1-1 cell line, was used to investigate cellular and molecular responses to prion infection. The MAP kinase cascade was dissected to assess the phosphorylation levels of src, MEK 1/2 and ERK 1/2 signaling molecules, both before and after prion infection. Our findings suggest that prion replication leads to a hyper-activation of this pathway. Biochemical analysis was complemented with immunofluorescence studies to map the localization of the ERK complex within the different cellular compartments. We showed how the ERK complex relocates in the cytosol upon prion infection. We correlated these findings with an impairment of cell growth in prion-infected GT1-1 cells as probed by MTT assay. Furthermore, given the persistent urgency in finding compounds able to cure prion infected cells, we tested the effects on the ERK cascade of two molecules known to block prion replication in vitro, quinacrine and Fab D18. We were able to show that while these two compounds possess similar effects in curing prion infection, they affect the MAP kinase cascade differently.Taken together, our results help shed light on the molecular events involved in neurodegeneration and neuronal loss in prion infection and replication. In particular, the combination of chronic activation and aberrant localization of the ERK complex may lead to a lack of essential neuroprotective and survival factors. Interestingly, these data seem to define some common traits with other neurodegenerative disorders such as, for example, Alzheimer's disease.
BRD4 Sustains Melanoma Proliferation and Represents a New Target for Epigenetic Therapy
Authors: Miguel F. Segura, Bárbara Fontanals-Cirera, Avital Gaziel-Sovran, María V. Guijarro, Doug Hanniford, Guangtao Zhang, Pilar González-Gomez, Marta Morante, Luz Jubierre, Weijia Zhang, Farbod Darvishian, Michael Ohlmeyer, Iman Osman, Ming-Ming Zhou, Eva Hernando
Journal: Cancer Research (2013)

Metastatic melanoma remains a mostly incurable disease. Although newly approved targeted therapies are efficacious in a subset of patients, resistance and relapse rapidly ensue. Alternative therapeutic strategies to manipulate epigenetic regulators and disrupt the transcriptional program that maintains tumor cell identity are emerging. Bromodomain and extraterminal domain (BET) proteins are epigenome readers known to exert key roles at the interface between chromatin remodeling and transcriptional regulation. Here, we report that BRD4, a BET family member, is significantly upregulated in primary and metastatic melanoma tissues compared with melanocytes and nevi. Treatment with BET inhibitors impaired melanoma cell proliferation in vitro and tumor growth and metastatic behavior in vivo, effects that were mostly recapitulated by individual silencing of BRD4. RNA sequencing of BET inhibitor-treated cells followed by Gene Ontology analysis showed a striking impact on transcriptional programs controlling cell growth, proliferation, cell-cycle regulation, and differentiation. In particular, we found that, rapidly after BET displacement, key cell-cycle genes (SKP2, ERK1, and c-MYC) were downregulated concomitantly with the accumulation of cyclin-dependent kinase (CDK) inhibitors (p21 and p27), followed by cell-cycle arrest. Importantly, BET inhibitor efficacy was not influenced by BRAF or NRAS mutational status, opening the possibility of using these small-molecule compounds to treat patients for whom no effective targeted therapy exists. Collectively, our study reveals a critical role for BRD4 in melanoma tumor maintenance and renders it a legitimate and novel target for epigenetic therapy directed against the core transcriptional program of melanoma.
Theory and Practice in the Use of a Pump-Oxygenator for Open Intracardiac Surgery
Authors: J. W. Kirklin, R. T. Patrick, R. A. Theye
Journal: Thorax (1957)

It is now accepted that certain intracardiac operations are best accomplished with the aid of a mechanical pump-oxygenator for the extracorporeal circulation and oxygenation of blood.There is not general agreement on either the theory or practice of establishing the extracorporeal circulation.Perhaps at this stage there is merit in recording some of the conclusions arrived at by one group after five years of experimental study in animals and two years of clinical experience embracing operations using this technique in 200 patients.This presentation omits experimental details, protocol of cases, and statistical analysis of results.Concepts and techniques presented are, of course, subject to modification by further data and ex- perience.Although the authors bear full respon- sibility for the views presented, which might in some instances be challenged even by members of their own group, these views have been the result not only of their own observations and investigations, but also that of their colleagues in the Mayo Clinic.These include Dr. D.
Acute lymphoblastic leukemia in the elderly: The Edouard Herriot hospital experience
Authors: Xavier Thomas, Nicoleta Olteanu, Christiane Charrin, Véronique Lhéritier, Jean‐Pierre Magaud, Denis Fiere
Journal: American Journal of Hematology (2001)

Data on all patients with acute lymphoblastic leukemia (ALL) aged 60 or older, referred to our institution over a 18-year period, were studied to determine the incidence and range of clinical and biological subtypes, and the outcome of different therapeutic approaches. Sixty-nine ALL cases (median age: 68 years) were diagnosed between 1980 and 1998 (18% of all adult ALL seen during this period). Ten of them (14%) had a past history of previous malignancy. Karyotypic analysis was performed successfully in 42 cases. Ten patients were diagnosed as Philadelphia chromosome positive (Ph(+)) ALL. Immunophenotyping was performed in 63 cases. Fifty-six patients had B-cell lineage ALL. T lymphoid markers were observed only in 5 cases. Co-expression of myeloid markers was observed in 19% of tested cases. Five patients died before any chemotherapy could be given. All other patients received "curative" treatment according to different protocols used during the period of study. Overall complete remission (CR) rate of these patients was 62% (95% confidence interval (CI): 50-74%). Thirty-nine patients achieved CR after one course of chemotherapy and 4 patients after salvage therapy. Median disease-free survival (DFS) of the entire cohort was 8.3 months (95% CI: 5-12.8 months) and median overall survival was 7 months (95% CI: 6-10 months). In multivariate analysis, the presence of hemorrhage (P = 0.02) was a poor prognostic for CR achievement. Higher WHO performance status (P = 0.003) and the presence of hemorrhage (P = 0.01) at diagnosis were poor prognostics for overall survival. When patients were stratified into three groups according to the time of admission, survival appeared significantly longer for patients admitted between July 1992 and December 1998 (median overall survival at 10 months) than for patients admitted before July 1992 (P = 0.04). "Age-adapted" therapy appeared superior to "young adult-like" therapy in terms of CR rate (96% versus 60%; P = 0.007). However, "age-adapted" therapy did not show any advantage in terms of DFS or overall survival, making the difference in CR rates questionable. We conclude that the pejorative overall outcome in elderly ALL points to the need for new therapeutic trials taking into account the specific characteristics of ALL in this age group.
Proceedings: Mobility, end-plate defects, and disc degeneration in the lower spine.
Authors: R C Hilton, J Ball
Journal: Annals of the Rheumatic Diseases (1975)

Systemic sclerosis (SSc) and vibration induced white finger syndrome (VWF) are common causes of secondary Raynaud9s phenomenon. Previous studies have suggested an increase in inflammation in patients with SSc. Vibration induced white finger syndrome occurs in workers exposed to vibration and is now a prescribed disease. In VWF, although it is recognised that vibration can cause direct damage to blood vessels, it does not explain why only some workers are affected. It is possible that an inflammatory process develops in these patients in the same way as is seen in SSc. Leukotriene B4, produced mainly by polymorphonuclear cells, is a potent mediator of inflammation. The plasma thiol concentration shows the degree of oxidation of plasma and a decreased concentration indicates the increased production of free radicals which are capable of oxidative damage. In this work, the white blood cell (WBC) production of leukotriene B4 and plasma thiol concentrations were measured in patients with SSc and VWF. Fifty nine patients were studied: 34 had SSc and 25 had VWF. The results were compared with 25 matched normal controls and are expressed as the median and range. After stimulation of the polymorphonuclear cells with calcium ionophore A23187 (1 microgram/ml), patients with SSc and VWF were found to have significantly increased leukotriene B4 production (23.5 (14.4-44.0) and 26 (14.4-39.4) ng/10(6) cells, respectively) compared with normal controls (17.2 (6.0-38.0) ng/10(6) cells). The plasma thiol concentration was shown to be significantly lower in patients with SSc and VWF (445 (375-475) and 450 (417-510) mumol/l, respectively) compared with normal controls (480 (418-555) mumol/l). Our results show increased leukotriene B4 production and increased free radical activity in patients with SSc and VWF. Although previous indirect evidence has suggested increased WBC activity in patients with SSc, this is reported directly here for the first time. In addition, the possibility of an inflammatory process occurring in patients with VWF, as shown here, has not previously been studied. This may be a further mechanism to explain the poor circulation in the fingers of these patients.
Nutrition and respiratory health in children in six Central and Eastern European countries
Authors: T Antova
Journal: Thorax (2003)

The results of studies on the effect of nutrition on respiratory diseases are inconsistent. The role of nutrition in children's respiratory health was therefore analysed within the cross sectional Central European Study on Air Pollution and Respiratory Health (CESAR).A total of 20 271 children aged 7-11 were surveyed in six European countries. Respiratory health and food intake were assessed using questionnaires. Associations between four symptoms and nutritional factors were evaluated using logistic regression, controlling for area plus other potential confounders.All symptoms showed initial associations with nutritional factors. Low consumption of fish and of summer and winter fruit were the most consistent predictors. In a fully adjusted model low fish intake remained a significant independent predictor of persistent cough (OR=1.18; 95% CI 1.04 to 1.34), wheeze ever (OR=1.14; 95% CI 1.03 to 1.25) and current wheeze (OR=1.21; 95% CI 1.06 to 1.39) and a weaker predictor of winter cough (OR=1.10; 95% CI 0.99 to 1.23). Low summer fruit intake was a predictor of winter cough (OR=1.40; 95% CI 1.10 to 1.79) and persistent cough (OR=1.35; 95% CI 1.01 to 1.82). Low winter fruit intake was associated with winter cough (OR=1.28; 95% CI 1.09 to 1.51). Associations between symptoms and vegetable intake were inconsistent. Low summer intake was significantly associated with winter cough (OR=1.23; 95% CI 1.03 to 1.47) but, overall, winter intake had inverse associations with both coughs. Associations between winter vegetable intake and wheeze varied considerably between countries.A number of associations were found between respiratory symptoms and low intake of fish, fruit and vegetables in children. Low fish intake was the most consistent predictor of poor respiratory health. Fruit and vegetable intake showed stronger associations with cough than with wheeze.
TCT-276 Safety of diagnostic transradial cardiac catheterization of outpatients under oral anticoagulation with Acenocumarol.
Authors: Juan Gabriel Cordoba Soriano, Arsenio Gallardo, Antonio Gutierrez Díez, isabel López Neyra, Cristina Llanos Guerrero, Manuel Fernández Anguita, Francisco Salmeron, Raquel Fuentes Manso, Driss Melehi, Jesús Jiménez Mazuecos
Journal: Journal of the American College of Cardiology (2013)
Cardiac Metabolism in Heart Failure
Authors: Torsten Doenst, Tien Dung Nguyen, E. Dale Abel
Journal: Circulation Research (2013)

The heart has a high rate of ATP production and turnover that is required to maintain its continuous mechanical work. Perturbations in ATP-generating processes may therefore affect contractile function directly. Characterizing cardiac metabolism in heart failure (HF) revealed several metabolic alterations called metabolic remodeling, ranging from changes in substrate use to mitochondrial dysfunction, ultimately resulting in ATP deficiency and impaired contractility. However, ATP depletion is not the only relevant consequence of metabolic remodeling during HF. By providing cellular building blocks and signaling molecules, metabolic pathways control essential processes such as cell growth and regeneration. Thus, alterations in cardiac metabolism may also affect the progression to HF by mechanisms beyond ATP supply. Our aim is therefore to highlight that metabolic remodeling in HF not only results in impaired cardiac energetics but also induces other processes implicated in the development of HF such as structural remodeling and oxidative stress. Accordingly, modulating cardiac metabolism in HF may have significant therapeutic relevance that goes beyond the energetic aspect.
Gemcitabine, Carboplatin, and Paclitaxel for Patients With Carcinoma of Unknown Primary Site: A Minnie Pearl Cancer Research Network Study
Authors: F. Anthony Greco, Howard A. Burris, Sharlene Litchy, John H. Barton, James E. Bradof, Paul Richards, Daniel C. Scullin, Joan B. Erland, Lisa H. Morrissey, John D. Hainsworth
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To evaluate the efficacy and toxicity of the novel chemotherapy combination that includes gemcitabine, carboplatin, and paclitaxel in the treatment of patients with carcinoma of unknown primary site. PATIENTS AND METHODS: One hundred twenty patients were treated with the following regimen, administered every 21 days for a planned four courses: gemcitabine 1,000 mg/m 2 intravenously (IV) on days 1 and 8, carboplatin at an estimated area under the concentration-time curve of 5 mg min/mL IV on day 1, and paclitaxel 200 mg/m 2 IV on day 1. After four courses, stable and responding patients were given weekly paclitaxel 70 mg/m 2 IV for 6 weeks for three 8-week courses. All patients had relatively poor prognostic features. Sixty-three patients had well-differentiated adenocarcinoma, 56 patients had poorly differentiated carcinoma, and 104 patients had performance status of 0 or 1. RESULTS: Twenty-eight (25%) of 113 assessable patients (95% confidence interval, 22% to 30%) had major objective responses to treatment. Response rates were similar in the two major histologic types. Response rate did not seem to be improved by continued therapy with weekly paclitaxel. The median progression-free survival time was 6 months. Median survival for the entire group was 9 months, and the actuarial survival at 1 and 2 years was 42% and 23%, respectively. CONCLUSION: Combination chemotherapy with gemcitabine, carboplatin, and paclitaxel followed by weekly paclitaxel is an active and tolerable treatment for patients with carcinoma of unknown primary site. The survival seen in this poor-prognosis group of patients in this multicenter community-based trial is notable and similar to other taxane-based regimens for these patients. Study of additional combinations or sequences of newer drugs, as well as the exploration of targeted biologic agents for patients with an identified target in their tumors, is warranted.