tbuckley/cabot-search huggingface dataset:
Inhibition of bone marrow colony formation by human natural killer cells and by natural killer cell-derived colony-inhibiting activity.
Authors: G Degliantoni, B Perussia, L Mangoni, G Trinchieri
Journal: The Journal of Experimental Medicine (1985)

Incubation of human peripheral blood lymphocytes with bone marrow cells resulted in significant inhibition of colony formation by committed myeloid and erythroid cells. Using positively selected homogeneous natural killer (NK) cell preparations and lymphocyte subpopulations depleted of or enriched for NK cells, we definitively characterize as NK cells the cells in normal peripheral blood that are responsible for inhibition of bone marrow colony growth. The inhibitory effect of NK cells on hematopoiesis can be mediated by a soluble factor that is produced only by NK cells upon culture with HLA-DR+ hematopoietic cells and with NK-sensitive cell lines. Both NK cells and the NK-produced, colony-inhibiting activity (NK-CIA) are suppressive for allogeneic and autologous bone marrow CFU-GEMM (colony-forming units, granulocyte, erythroid, monocyte, megakaryocyte), CFU-E (CFU, erythroid), and early CFU-GM (CFU, granulocyte, monocyte), but not for either BFU-E (burst-forming units, erythroid) or late CFU-GM. [3H]Thymidine incorporation was inhibited by NK-CIA-containing supernatants in HLA-DR+ but not HLA-DR- bone marrow cell populations stimulated to proliferative by colony-stimulating factor (CSF). These data suggest that the NK cell-mediated inhibitory effect on proliferation and differentiation of hematopoietic precursor cells is mediated in part or completely by the secreted NK-CIA. The concentration of NK-CIA reached in the supernatant of the mixture of NK cell-containing lymphocyte populations with bone marrow cells is sufficient to account for the inhibitory effect mediated by NK cells. Our data support the hypothesis that human NK cells play a major role in the control of hematopoiesis, down-regulating it under conditions in which the NK cells are functionally activated.
Trifunctional Bispecific Antibodies Induce Tumor-Specific T Cells and Elicit a Vaccination Effect
Authors: Nina Eissler, Peter Ruf, Josef Mysliwietz, Horst Lindhofer, Ralph Mocikat
Journal: Cancer Research (2012)

A major goal of tumor immunotherapy is the induction of long-lasting systemic T-cell immunity. Bispecific antibodies (bsAbs) that lack the immunoglobulin Fc region confer T-cell-mediated killing of tumor cells but do not induce long-term memory. In contrast, trifunctional bsAbs comprise an appropriate Fc region and, therefore, not only recruit T cells but also accessory cells that bear activating Fcγ receptors (FcγR), providing additional T-cell-activating signals and securing presentation of tumor-derived antigens to T cells. In this study, we show that trifunctional bsAbs induce a polyvalent T-cell response and, therefore, a vaccination effect. Mice were treated with melanoma cells and with a trifunctional bsAb directed against the melanoma target antigen ganglioside GD2 in addition to murine CD3. The trifunctional bsAb activated dendritic cells and induced a systemic immune response that was not replicated by treatment with the F(ab')2-counterpart lacking the Fc region. Restimulation of spleen and lymph node cells in vitro yielded T-cell lines that specifically produced interferon-γ in response to tumor. In addition, trifunctional bsAb-induced T cells recognized various specific peptides derived from melanoma-associated antigens. Moreover, these polyvalent responses proved to be tumor-suppressive and could not be induced by the corresponding bsF(ab')2-fragment. Taken together, our findings provide preclinical proof of concept that trifunctional bsAbs can induce tumor-specific T cells with defined antigen specificity.
Meta-analysis of cardiovascular disease risk markers in women with polycystic ovary syndrome
Authors: Konstantinos A. Toulis, Dimitrios G. Goulis, Gesthimani Mintziori, Evangelia Kintiraki, Evangelos Eukarpidis, Sophia-Anastasia Mouratoglou, Antigoni Pavlaki, Stavros Stergianos, Maria Poulasouchidou, Thrasivoulos G. Tzellos, Anastasios Makedos, Michael Chourdakis, Basil C. Tarlatzis
Journal: Human Reproduction Update (2011)

The relation between polycystic ovary syndrome (PCOS) and cardiovascular disease (CVD) remains unclear. In an attempt to provide high-quality evidence on the relation between PCOS and CVD, relevant literature for CVD risk markers [C-reactive protein (CRP), homocysteine (Hcy), tumor necrosis factor-alpha (TNF-α), plasminogen activator inhibitor-1 (PAI-1), lipoprotein (a) [Lp(a)], advanced glycation end-products (AGEs), vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), asymmetric dimethylarginine (ADMA), endothelin-1 (ET-1) and fibrinogen] in women with PCOS was reviewed and analyzed. A systematic search was conducted electronically using specific eligibility criteria. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated and combined appropriately. To ensure synthesis of the best available evidence, sensitivity analyses were performed. A total of 130 data sets were included in 11 different outcomes, involving 7174 and 5076 CVD markers in women with PCOS and controls, respectively. Women with PCOS demonstrated significantly elevated CRP [WMD (95% CI) 0.99 (0.77–1.21)], Hcy [2.25 (1.46–3.03)], PAI-1 antigen [16.96 (7.25–26.28)], PAI-1 activity [0.71 (0.18–1.23)], VEGF [1.72 (0.96–2.48)], ADMA [0.19 (0.08–0.3)], AGEs [3.91 (2.36–5.45)] and Lp(a) [0.81 (0.58–1.04)] concentrations compared with controls, yet with significant between-study heterogeneity. Borderline significance (not robust in the sensitivity analyses) was detected for TNF-α [0.75 (0.07–1.44)], ET-1 [1.06 (0.52–1.59)] and fibrinogen [0.20 (0.01–0.39)], whereas no difference was detected for IL-6 [0.71 (−0.16 to 1.59)]. Women with PCOS have increased serum concentrations of CVD risk markers compared with controls. Whether this apparent risk is translated into increased incidence of CVD in later life remains to be elucidated.
Bevacizumab plus Radiotherapy–Temozolomide for Newly Diagnosed Glioblastoma
Authors: Olivier L Chinot, Wolfgang Wick, Warren Mason, Roger Henriksson, Frank Saran, Ryo Nishikawa, Antoine F Carpentier, Khe Hoang-Xuan, Petr Kavan, Dana Cernea, Alba A Brandes, Magalie Hilton, Lauren Abrey, Timothy Cloughesy
Journal: New England Journal of Medicine (2014)

Standard therapy for newly diagnosed glioblastoma is radiotherapy plus temozolomide. In this phase 3 study, we evaluated the effect of the addition of bevacizumab to radiotherapy-temozolomide for the treatment of newly diagnosed glioblastoma.We randomly assigned patients with supratentorial glioblastoma to receive intravenous bevacizumab (10 mg per kilogram of body weight every 2 weeks) or placebo, plus radiotherapy (2 Gy 5 days a week; maximum, 60 Gy) and oral temozolomide (75 mg per square meter of body-surface area per day) for 6 weeks. After a 28-day treatment break, maintenance bevacizumab (10 mg per kilogram intravenously every 2 weeks) or placebo, plus temozolomide (150 to 200 mg per square meter per day for 5 days), was continued for six 4-week cycles, followed by bevacizumab monotherapy (15 mg per kilogram intravenously every 3 weeks) or placebo until the disease progressed or unacceptable toxic effects developed. The coprimary end points were investigator-assessed progression-free survival and overall survival.A total of 458 patients were assigned to the bevacizumab group, and 463 patients to the placebo group. The median progression-free survival was longer in the bevacizumab group than in the placebo group (10.6 months vs. 6.2 months; stratified hazard ratio for progression or death, 0.64; 95% confidence interval [CI], 0.55 to 0.74; P<0.001). The benefit with respect to progression-free survival was observed across subgroups. Overall survival did not differ significantly between groups (stratified hazard ratio for death, 0.88; 95% CI, 0.76 to 1.02; P=0.10). The respective overall survival rates with bevacizumab and placebo were 72.4% and 66.3% at 1 year (P=0.049) and 33.9% and 30.1% at 2 years (P=0.24). Baseline health-related quality of life and performance status were maintained longer in the bevacizumab group, and the glucocorticoid requirement was lower. More patients in the bevacizumab group than in the placebo group had grade 3 or higher adverse events (66.8% vs. 51.3%) and grade 3 or higher adverse events often associated with bevacizumab (32.5% vs. 15.8%).The addition of bevacizumab to radiotherapy-temozolomide did not improve survival in patients with glioblastoma. Improved progression-free survival and maintenance of baseline quality of life and performance status were observed with bevacizumab; however, the rate of adverse events was higher with bevacizumab than with placebo. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT00943826.).
Ischemic but Not Pharmacological Preconditioning Requires Protein Synthesis
Authors: N Matsuyama, J E Leavens, D McKinnon, G R Gaudette, T O Aksehirli, I B Krukenkamp
Journal: Circulation (2000)

Ischemic preconditioning (IPC) and pharmacological preconditioning (PPC) have both been shown to confer cardioprotective effects. However, the role of protein synthesis in preconditioning is unclear.Isolated rabbit hearts were treated with cycloheximide (CHx, 10 micromol/L), a protein synthesis inhibitor at the translational level, before 2 cycles of IPC (5 minutes of global ischemia/5 minutes of reperfusion, n=6) or PPC by pinacidil (PIN, 10 micromol/L; n=6), an ATP-sensitive potassium channel opener. Six rabbit hearts received actinomycin D (Act D, 20 micromol/L; n=6), a protein synthesis inhibitor at the transcriptional level, before IPC. The left anterior descending coronary artery was then occluded for 60 minutes and reperfused for 120 minutes. Control hearts received no treatment before prolonged ischemia (n=6). Left ventricular pressure, action potential duration, and coronary flow were measured. Infarct size is expressed as a percentage of the area at risk. IPC (n=6) and PIN (n=8) hearts experienced reduced infarct size compared with control hearts (22+/-3% and 27+/-2% versus 46+/-3%, IPC and PIN versus control; P:<0.01). Translational blockade (CHx) reversed the IPC infarct size reduction effect (22+/-3% versus 48+/-4%, IPC versus CHx+IPC; P:<0.01) but not the effects of pinacidil (27+/-2% versus 29+/-3%, PIN versus CHx+PIN; P:=NS). Transcriptional blockade (Act D) did not abolish the IPC effect (23+/-5% versus 22+/-3%, Act D+IPC versus IPC; P:=NS). There were no significant differences in electromechanical function consequent to CHx and Act D treatment.These findings suggest an important role for protein synthesis in the mechanism for IPC-mediated protection at the translational level, which may be different from PPC.
Nanoparticles Containing a Liver X Receptor Agonist Inhibit Inflammation and Atherosclerosis
Authors: Xue‐Qing Zhang, Orli Even‐Or, Xiaoyang Xu, Mariska van Rosmalen, Lucas Lim, Suresh Gadde, Omid C. Farokhzad, Edward A. Fisher
Journal: Advanced Healthcare Materials (2014)

Liver X receptor (LXR) signaling pathways regulate lipid metabolism and inflammation, which has generated widespread interest in developing synthetic LXR agonists as potential therapeutics for the management of atherosclerosis. In this study, it is demonstrated that nanoparticles (NPs) containing the synthetic LXR agonist GW3965 (NP‐LXR) exert anti‐inflammatory effects and inhibit the development of atherosclerosis without causing hepatic steatosis. These NPs are engineered through self‐assembly of a biodegradable diblock poly(lactide‐ co ‐glycolide)‐ b ‐poly(ethylene glycol) (PLGA‐ b ‐PEG) copolymer. NP–LXR is significantly more effective than free GW3965 at inducing LXR‐target gene expression and suppressing inflammatory factors in macrophages in vitro and in vivo. Additionally, the NPs elicit negligible lipogenic gene stimulation in the liver. Using the Ldlr −/− mouse model of atherosclerosis, abundant colocalization of fluorescently labeled NPs within plaque macrophages following systemic administration is seen. Notably, six intravenous injections of NP–LXR over 2 weeks markedly reduce the CD68‐positive cell (macrophage) content of plaques (by 50%) without increasing total cholesterol or triglycerides in the liver and plasma. Together, these findings identify GW3965‐encapsulated PLGA‐ b ‐PEG NPs as a promising nanotherapeutic approach to combat atherosclerosis, providing the benefits of LXR agonists without their adverse effects on hepatic and plasma lipid metabolism.
Stress and Health: Psychological, Behavioral, and Biological Determinants
Authors: Neil Schneiderman, Gail Ironson, Scott D. Siegel
Journal: Annual Review of Clinical Psychology (2004)

Stressors have a major influence upon mood, our sense of well-being, behavior, and health. Acute stress responses in young, healthy individuals may be adaptive and typically do not impose a health burden. However, if the threat is unremitting, particularly in older or unhealthy individuals, the long-term effects of stressors can damage health. The relationship between psychosocial stressors and disease is affected by the nature, number, and persistence of the stressors as well as by the individual's biological vulnerability (i.e., genetics, constitutional factors), psychosocial resources, and learned patterns of coping. Psychosocial interventions have proven useful for treating stress-related disorders and may influence the course of chronic diseases.
Predicting Productivity Returns on Investment
Authors: Michael S. Lauer, Narasimhan S. Danthi, Jonathan Kaltman, Colin Wu
Journal: Circulation Research (2015)

There are conflicting data about the ability of peer review percentile rankings to predict grant productivity, as measured through publications and citations. To understand the nature of these apparent conflicting findings, we analyzed bibliometric outcomes of 6873 de novo cardiovascular R01 grants funded by the National Heart, Lung, and Blood Institute (NHLBI) between 1980 and 2011. Our outcomes focus on top-10% articles, meaning articles that were cited more often than 90% of other articles on the same topic, of the same type (eg, article, editorial), and published in the same year. The 6873 grants yielded 62 468 articles, of which 13 507 (or 22%) were top-10% articles. There was a modest association between better grant percentile ranking and number of top-10% articles. However, discrimination was poor (area under receiver operating characteristic curve [ROC], 0.52; 95% confidence interval, 0.51–0.53). Furthermore, better percentile ranking was also associated with higher annual and total inflation-adjusted grant budgets. There was no association between grant percentile ranking and grant outcome as assessed by number of top-10% articles per $million spent. Hence, the seemingly conflicting findings on peer review percentile ranking of grants and subsequent productivity largely reflect differing questions and outcomes. Taken together, these findings raise questions about how best National Institutes of Health (NIH) should use peer review assessments to make complex funding decisions.
Curcumin against hepatitis C virus infection: spicing up antiviral therapies with ‘nutraceuticals’?
Authors: Eve-Isabelle Pécheur
Journal: Gut (2013)

Infection with the HCV is one of the major causes of chronic liver disease with an estimated 184 million persons worldwide positive for HCV antibodies1 and 3–4 million newly infected each year. The situation is worrying in emerging countries of Central and Southeast Asia, North Africa and Middle East with seroprevalence around 3%–5%. Central Africa and Egypt remain regions of very high endemicity with a 25% prevalence in the latter. Hepatitis C is therefore a global health problem with striking inequalities in the access to healthcare and implementation of treatments between world regions.

HCV is an enveloped RNA virus classified into seven genotypes, and virions are found associated to β-lipoproteins in the serum of patients.2 A generally asymptomatic initial infection phase is followed by signs of liver injury after 20–30 years, and patients develop cirrhosis or hepatocellular carcinoma in severe cases for which liver transplantation (LT) is the only alternative. In the absence of preventive vaccine, the current standard of care treatment relies on a combination of interferon α (IFNα) and ribavirin, to which direct-acting antivirals (DAA) have been recently added. DAA target viral enzymes of the replication complex and raise great hopes of eradication in treated patients. At present, filed DAA are only effective on genotype 1, induce viral resistance and severe adverse effects, and their costs are out of reach for patients of emerging countries.3 Novel DAA currently in clinical trials are pan-genotypic and usable in IFN-free regimens in a near-future perspective of all-oral therapies.3 HCV-positive patients undergoing LT experience graft infection and recurrence of hepatitis C, shortening their survival compared with uninfected transplant recipients.4 In these particular clinical cases, antiviral therapies aimed at preventing …
Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions
Authors: Mathieu Lafourcade, Thomas Larrieu, Susana Mato, Anais Duffaud, Marja Sepers, Isabelle Matias, Veronique De Smedt-Peyrusse, Virginie F Labrousse, Lionel Bretillon, Carlos Matute, Rafael Rodríguez-Puertas, Sophie Layé, Olivier J Manzoni
Journal: Nature Neuroscience (2011)
Increased Fibronectin Deposition in Embryonic Hearts of Retinol-Binding Protein–Null Mice
Authors: Christopher C. Wendler, Angela Schmoldt, George R. Flentke, Lauren C. Case, Loredana Quadro, William S. Blaner, John Lough, Susan M. Smith
Journal: Circulation Research (2003)

Precise regulation of retinoid levels is critical for normal heart development. Retinol-binding protein (RBP), an extracellular retinol transporter, is strongly secreted by cardiogenic endoderm. This study addresses whether RBP gene ablation affects heart development. Despite exhibiting an >85% decrease in serum retinol, adult RBP-null mice are viable, breed, and have normal vision when maintained on a vitamin A-sufficient diet. Comparison of RBP-null with wild-type (WT) hearts from embryos at day 9.0 (E9.0) through E12.5 revealed an RBP-null phenotype similar to that of other retinoid-deficient models. At an early stage, RBP-null hearts display retarded trabecular development, which recovers by E9.5. This is accompanied at E9.5 and E10.5 by precocious differentiation of subepicardial cardiac myocytes. Most remarkably, RBP-null hearts display augmented deposition of fibronectin protein in the cardiac jelly at E9.0 through E10.5 and in the outflow tract at E12.5. This phenomenon, which was detected by immunohistochemistry and Western blotting without increased fibronectin transcript levels, is accompanied by increased numbers of mesenchymal cells in the outflow tract but not in the atrioventricular canal. RBP-null cardiac myocytes, especially in the subepicardial layer, display increased cell proliferation. This phenotype may present a model of subclinical retinoid insufficiency characterized by alteration of an extracellular matrix component and altered cellular differentiation and proliferation, changes that may have functional consequences for adult cardiac function. This murine model may have relevance to fetal development in human populations with inadequate retinoid intake.
Trophic Mechanisms in the Peripheral Nervous System
Authors: Silvio S. Varon, Richard P. Bunge
Journal: Annual Review of Neuroscience (1978)

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
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study of the Efficacy of Omalizumab in Prevention of Bronchoconstriction Following Environmental Aeroallergen Exposure
Authors: J. Corren, R.A. Wood, D. Patel, J. Zhu, J.E. Fish
Journal: Journal of Allergy and Clinical Immunology (2010)
Can Schizophrenia Change to Affective Psychosis?
Authors: EUGENE ZISKIND, ESTHER SOMERFELD, RUTH JENS
Journal: American Journal of Psychiatry (1971)

Five patients diagnosed as schizophrenic 15 to 30 years ago by the authors have been treated intermittently since then for frequent periodic attacks. Each patient has undergone marked improvement. On maintenance medication there are very few (usually two to 14) days of illness each year. The most striking change is that their symptoms are now primarily affective in character rather than schizophrenic.
Prevalence of Adult-Onset IDDM in the U.S. Population
Authors: Maureen I Harris, David C Robbins
Journal: Diabetes Care (1994)

To investigate the prevalence of adult-onset insulin-dependent diabetes mellitus (IDDM) in a nationally representative sample of adults 30-74 years of age. Although it is a widely held belief that onset of IDDM in adults is rare, there are few objective data to support this. Adult-onset IDDM may represent a disease that is biologically distinct from youth-onset IDDM, and it would be important to distinguish these two entities.The Second National Health and Nutrition Examination Survey (NHANES II) contained a national probability sample of 12,102 subjects 30-74 years of age in the U.S. population. All subjects with diabetes diagnosed by a physician before the survey were identified. Cases of IDDM defined by age at diagnosis > or = 30 years, continuous or nearly continuous insulin treatment since diagnosis of diabetes, and relative body weight < or = 125 were classified as adult-onset IDDM.Subjects with adult-onset IDDM represented 0.30% of the U.S. population 30-74 years of age and 7.4% of all diabetic patients diagnosed at 30-74 years of age.These data indicate that onset of IDDM in adults is uncommon. Given the limitations of the survey instrument, subclinical or slowly progressive IDDM (as distinguished from non-insulin-dependent diabetes mellitus with progressive loss of beta-cell function) would not have been detected, and these would constitute additional cases of adult-onset IDDM. However, the data suggest that a very large population base would be required to identify sufficient numbers of adult-onset IDDM cases for study of the etiology and pathogenesis of this disease.