tbuckley/cabot-search huggingface dataset:
Triggering of affinity-enriched B cells. Analysis of B cell stimulation by antigen-specific helper factor or lipopolysaccharide. I. Dissection into proliferative and differentiative signals.
Authors: M A Jaworski, C Shiozawa, E Diener
Journal: The Journal of Experimental Medicine (1982)

Proliferative and differentiative signals controlling the in vitro IgM response by unprimed, affinity-enriched B cells were studied using conditions under which as few as 2,000 B cells stimulated by antigen-specific, Ia-positive, allogeneically restricted, T cell-derived helper factor (Hf) or the polyclonal activator lipopolysaccharide (LPS) yielded on the average 400 antibody-forming cells (AFC) by direct plaque assay. Antigen alone induces neither B cell proliferation nor differentiation into AFC. Proliferation but not differentiation into AFC is induced when affinity-enriched B cells are cultured in the presence of Ag and Hf or LPS but in the absence of nonantigen-specific, radioresistant, accessory (A) cells. For the induction of a complete Hf- or LPS-mediated AFC response, cultures must be reconstituted with A cells or the secretory product(s) of these cells. The antigen-specific response depends strictly on the presence of the Hf specific for the relevant antigen, regardless of the cell cycle state of cooperating B cells. The differentiative signal from A cells is due, at least in part, to the presence of a Thy-1.2-bearing population of cells. In the case of the LPS-mediated, but not the Hf-mediated response. A cells can be substituted by using supernatant derived from an interleukin 2-secreting T lymphoma cell line (EL4). In the presence of histocompatible Hf and B cells, histoincompatible A cells can still cooperate in the immune response. However, the degree of allogeneic restriction between incompatible Hf and B cells is markedly increased if both B cells and A cells are incompatible with Hf.
Partitioning of inspiratory muscle workload and pressure assistance in ventilator-dependent COPD patients.
Authors: L Appendini, A Purro, A Patessio, S Zanaboni, M Carone, E Spada, C F Donner, A Rossi
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

To investigate the mechanisms underlying ventilator-dependence in patients with chronic obstructive pulmonary disease (COPD), and to assess the effects of the combination of positive end-expiratory pressure (PEEP) and pressure-support ventilation (PSV) on inspiratory muscle effort, we investigated respiratory mechanics in eight ventilator-dependent COPD patients. The patients' breathing pattern, lung mechanics, diaphragmatic effort (PTPdi), diaphragmatic tension-time index (TTdi), and arterial blood gases were measured during both spontaneous breathing (SB) and ventilatory assistance consisting of PSV alone (15, 20, and 25 cm H2O) and PSV combined with a PEEP of 5 cm H2O (reducing PSV to 10, 15, and 20 cm H2O, respectively, to maintain equivalent inspiratory pressure). The different levels of ventilatory support were delivered in a randomized sequence. Maximal inspiratory (MIP), esophageal (PpImax) and transdiaphragmatic (Pdi(max)) pressures and respiratory drive (P(0.1)) were measured at the beginning of the procedure during SB. We found a high P(0.1) (6.1 +/- 1.7 cm H2O), which seemed to rule out an impairment of respiratory-center output. Apparently, inspiratory muscle strength was compatible with successful weaning (38.5 +/- 8.8, 50.9 +/- 9.7, and 51.8 +/- 9.5 cm H2O for MIP, PPImax and Pdi(max), respectively). However, abnormal respiratory mechanics (particularly an intrinsic positive end-expiratory pressure (PEEPi) of 8.3 +/- 1.9 cm H2O and pulmonary resistance 24.7 +/- 9.5 cm H2O/L/s imposed an excessive load on the inspiratory muscles, as indicated by a high PTPdi (499 +/- 122 cm H2O x s). Increasing levels of PSV progressively and significantly unloaded the patients' inspiratory muscles, although at pressures above 20 cm H2O uncoupling occurred between patient and ventilator respiratory frequency. Application of PEEP during PSV improved ventilatory assistance by further reducing the inspiratory effort (by 17% on average) and by ameliorating patient-ventilator interaction. We conclude that the excessive mechanical load, and in particular the high PEEPi, is the major determinant of ventilator-dependence in COPD patients. Application of PEEP improves the efficiency of PSV in unloading these patients' inspiratory muscles, and can sometimes improve patient-ventilator interaction.
Extent of Laminin-5 Assembly and Secretion Effect Junctional Epidermolysis Bullosa Phenotype
Authors: Chihiro Matsui, Phyllis Pereira, C. Kathy Wang, Charlotte F. Nelson, Timothy Kutzkey, Caroline Lanigan, David Woodley, Masaaki Morohashi, Elizabeth A. Welsh, Warren K. Hoeffler
Journal: The Journal of Experimental Medicine (1998)

Junctional epidermolysis bullosa (JEB) is an autosomal recessive skin blistering disease with both lethal and nonlethal forms, with most patients shown to have defects in laminin-5. We analyzed the location of mutations, gene expression levels, and protein chain assembly of the laminin-5 heterotrimer in six JEB patients to determine how the type of genetic lesion influences the pathophysiology of JEB. Mutations within laminin-5 genes were diversely located, with the most severe forms of JEB correlating best with premature termination codons, rather than mapping to any particular protein domain. In all six JEB patients, the laminin-5 assembly intermediates we observed were as predicted by our previous work indicating that the alpha3beta3gamma2 heterotrimer assembles intracellularly via a beta3gamma2 heterodimer intermediate. Since assembly precedes secretion, mutations that disrupt protein-protein interactions needed for assembly are predicted to limit the secretion of laminin-5, and likely to interfere with function. However, our data indicate that typically the most severe mutations diminish mRNA stability, and serve as functional null alleles that block chain assembly by resulting in either a deficiency (in the nonlethal mitis variety) or a complete absence (in lethal Herlitz-JEB) of one of the chains needed for laminin-5 heterotrimer assembly.
Inducible Expression of Lectin-like Oxidized LDL Receptor-1 in Vascular Endothelial Cells
Authors: Noriaki Kume, Takatoshi Murase, Hideaki Moriwaki, Takuma Aoyama, Tatsuya Sawamura, Tomoh Masaki, Toru Kita
Journal: Circulation Research (1998)

Abstract —Endothelial dysfunction, or activation, elicited by oxidized LDL (Ox-LDL) or its lipid constituent, has been implicated in the initiation and progression of atherosclerosis. We have recently identified a C-type lectin-like molecule, designated lectin-like Ox-LDL receptor-1 (LOX-1), which acts as a cell-surface receptor for Ox-LDL in cultured vascular endothelial cells. In this study, we provide evidence that LOX-1 expression can be upregulated by tumor necrosis factor-α (TNF-α) and phorbol 12-myristate 13-acetate (PMA) in cultured bovine aortic endothelial cells. TNF-α and PMA upregulated LOX-1 protein and mRNA in a time- and dose-dependent manner. Nuclear runoff assay revealed that TNF-α stimulates transcription of the LOX-1 gene. Chinese hamster ovary K1 cells stably expressing LOX-1 internalized 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI)-labeled Ox-LDL but did not significantly internalize acetylated LDL (Ac-LDL), which was effectively suppressed by excess amounts of unlabeled Ox-LDL but not by Ac-LDL. Upregulated expression of LOX-1 by TNF-α and PMA was associated with increased uptake of DiI-Ox-LDL that cannot be blocked by excess amounts of unlabeled Ac-LDL. Taken together, LOX-1 is a receptor specific for Ox-LDL, and enhanced uptake of Ox-LDL via this novel receptor on vascular endothelial cells may play an important role in endothelial activation in atherogenesis.
Inactivation of the HIF-1α/PDK3 Signaling Axis Drives Melanoma toward Mitochondrial Oxidative Metabolism and Potentiates the Therapeutic Activity of Pro-Oxidants
Authors: Jérome Kluza, Paola Corazao-Rozas, Yasmine Touil, Manel Jendoubi, Cyril Maire, Pierre Guerreschi, Aurélie Jonneaux, Caroline Ballot, Stéphane Balayssac, Samuel Valable, Aurélien Corroyer-Dulmont, Myriam Bernaudin, Myriam Malet-Martino, Elisabeth Martin de Lassalle, Patrice Maboudou, Pierre Formstecher, Renata Polakowska, Laurent Mortier, Philippe Marchetti
Journal: Cancer Research (2012)

Cancer cells can undergo a metabolic reprogramming from oxidative phosphorylation to glycolysis that allows them to adapt to nutrient-poor microenvironments, thereby imposing a selection for aggressive variants. However, the mechanisms underlying this reprogramming are not fully understood. Using complementary approaches in validated cell lines and freshly obtained human specimens, we report here that mitochondrial respiration and oxidative phosphorylation are slowed in metastatic melanomas, even under normoxic conditions due to the persistence of a high nuclear expression of hypoxia-inducible factor-1α (HIF-1α). Pharmacologic or genetic blockades of the HIF-1α pathway decreased glycolysis and promoted mitochondrial respiration via specific reduction in the expression of pyruvate dehydrogenase kinase-3 (PDK3). Inhibiting PDK3 activity by dichloroacetate (DCA) or siRNA-mediated attenuation was sufficient to increase pyruvate dehydrogenase activity, oxidative phosphorylation, and mitochondrial reactive oxygen species generation. Notably, DCA potentiated the antitumor effects of elesclomol, a pro-oxidative drug currently in clinical development, both by limiting cell proliferation and promoting cell death. Interestingly, this combination was also effective against BRAF V600E-mutant melanoma cells that were resistant to the BRAF inhibitor vemurafenib. Cotreatment of melanomas with DCA and elesclomol in vivo achieved a more durable response than single agent alone. Our findings offer a preclinical validation of the HIF-1/PDK3 bioenergetic pathway as a new target for therapeutic intervention in metastatic melanoma, opening the door to innovative combinations that might eradicate this disease.
Eplin-alpha expression in human breast cancer, the impact on cellular migration and clinical outcome
Authors: Wen G Jiang, Tracey A Martin, Jo M Lewis-Russell, Anthony Douglas-Jones, Lin Ye, Robert E Mansel
Journal: Molecular Cancer (2008)

To investigate the expression of EPLIN-α, epithelial protein lost in neoplasm, in human breast cancer tissues/cells and investigate the cellular impact of EPLIN-α on breast cancer cells. EPLIN-α was determined in tumour (n = 120) and normal mammary tissues (n = 32), and cancer cell lines (n = 16). Cell invasion, in vitro and in vivo growth of cells transfected with EPLIN-α were evaluated using in vitro invasion assay, in vitro and in vivo tumour model. Cellular migration was analysed using Electric Cell Impedance Sensing assays. Low level of EPLIN-α was seen in tumour tissues. Grade-2/3 tumours had significantly lower levels of EPLIN-α compared with grade-1 (p = 0.047 and p = 0.046 vs grade-1, respectively). Patients with poor prognosis had a significantly lower levels of EPLIN-α compared with those with good prognosis (p = 0.0081). Patients who developed recurrence and died of breast cancer had significantly lower levels of EPLIN-α compared with those who remained disease free (p = 0.0003 and p = 0.0008, respectively) (median follow-up 10 years). Patients with high levels of EPLIN-α transcript had a longer survival than those with low levels. Over-expression of EPLIN-α in breast cancer cells by way of transfection rendered cells less invasive, less motile and growing at a slower pace in vitro and in vivo. An ERK inhibitor was shown to be able to abolish the effect of EPLIN expression. It is concluded that expression of EPLIN-α in breast cancer is down-regulated in breast cancer cells and tissues, a change linked to the prognosis. EPLIN-α acts as a potential tumour suppressor by inhibition of growth and migration of cancer cells.
In the Spotlight: Neuroengineering
Authors: Nitish V. Thakor
Journal: IEEE Reviews in Biomedical Engineering (2011)

Considering the high volume of publications and ever increasing attendance at the international conferences, including the 2012 Annual International Conference of the IEEE Engineering in Medicine and Biology Conference (IEEE EMBC 2012), Neuroengineering appears to be evolving as an independent discipline by itself. Continuing the legacy of the previous years' conferences, neuroengineering was one of the most represented topics at the IEEE EMBC 2012, held this year in San Diego, CA. Contributing to the interest were three workshops that focused on systems level concepts in neuroengineering: namely, Brain - Machine - Body Interfaces (led by Gert Cauwenberghs, University of California, San Diego), Brain Dynamics in Human Motor Control (led by David Peterson, University of California, San Diego) and Brain-Computer Interfaces and Electrocorticography (led by Robert Prueckl, Guger Technologies). These and other related works are briefly reviewed.
Giving blood: a new role for CD40 in tumorigenesis
Authors: Stephan Bergmann, Pier Paolo Pandolfi
Journal: The Journal of Experimental Medicine (2006)

CD40 was initially identified as a receptor expressed by B cells that is crucial for inducing an effective adaptive immune response. CD40 was subsequently shown to be expressed by endothelial cells and to promote angiogenesis. New data now show that in tumor-prone transgenic mice, CD40-mediated neovascularization is essential for early stage tumorigenicity. This suggests, at least in this mouse model, that CD40 has an important role in the angiogenic process that is coupled to carcinogenesis, a finding that could lead to novel therapeutic opportunities.
Anticardiolipin antibodies, livedo reticularis, and major cerebrovascular and renal disease in systemic lupus erythematosus.
Authors: N J McHugh, J Maymo, R P Skinner, I James, P J Maddison
Journal: Annals of the Rheumatic Diseases (1988)

Increased levels of IgG anticardiolipin antibodies (ACA) were found in 23 of 98 patients (23%) with systemic lupus erythematosus. Increased levels of IgM ACA were found less frequently (5%). All four patients with major cerebrovascular events had increased IgG ACA, including the two with highest levels, both of whom were men. Six of nine patients with livedo reticularis had increased IgG ACA. In turn, this clinical feature was associated with cerebrovascular disease in two and renal disease in another six. IgG ACA were not associated with other thromboembolic events, thrombocytopenia, serum IgG, or autoantibodies to Ro(SSA), La(SSB), U1RNP, Sm, or double or single stranded DNA.
Optimization of the Tet-on System To Regulate Interleukin 12 Expression in the Liver for the Treatment of Hepatic Tumors
Authors: Maider Zabala, Lin Wang, Ruben Hernandez-Alcoceba, Wolfgang Hillen, Cheng Qian, Jesus Prieto, M. Gabriela Kramer
Journal: Cancer Research (2004)

Abstract Interleukin 12 (IL-12) is a potent antitumoral cytokine, but it can be toxic at high doses. Therapy of liver tumors might benefit from the use of vectors enabling tight control of IL-12 expression in hepatic tissue for long periods of time. To this aim, we have improved the Tet-on system by modifying the minimal region of the inducible promoter and adjusting the level of the trans-activator using liver-specific promoters with graded activities. The resulting vectors allowed hepato-specific gene regulation with lower basal activity and higher inducibility compared with the original system in the absence of repressor molecules. The basal and final protein levels depend on the strength of the promoter that directs the transcripcional activator as well as the relative orientation of the two genes in the same plasmid. We have selected the construct combining minimal leakage with higher level of induced gene expression to regulate IL-12 after DNA transfer to mouse liver. Administration of doxycycline (Dox) enhanced IL-12 expression in a dose-dependent manner, whereas it was undetectable in serum in the noninduced state. Gene activation could be repeated several times, and sustained levels of IL-12 were achieved by daily administration of Dox. The antitumor effect of IL-12 was evaluated in a mouse model of metastatic colon cancer to the liver. Complete eradication of liver metastasis and prolonged survival was observed in all mice receiving Dox for 10 days. These data demonstrate the potential of a naked DNA gene therapy strategy to achieve tight control of IL-12 within the liver for the treatment of cancer.
Molecular Study of Malignant Gliomas Treated with Epidermal Growth Factor Receptor Inhibitors: Tissue Analysis from North American Brain Tumor Consortium Trials 01-03 and 00-01
Authors: Andrew B. Lassman, Michael R. Rossi, Jeffrey R. Razier, Lauren E. Abrey, Frank S. Lieberman, Chelsea N. Grefe, Kathleen Lamborn, William Pao, Alan H. Shih, John G. Kuhn, Richard Wilson, Norma J. Nowak, John K. Cowell, Lisa M. DeAngelis, Patrick Wen, Mark R. Gilbert, Susan Chang, W.A. Yung, Michael Prados, Eric C. Holland
Journal: Clinical Cancer Research (2005)

Abstract Purpose: We investigated the molecular effect of the epidermal growth factor receptor (EGFR) inhibitors erlotinib and gefitinib in vivo on all available tumors from patients treated on North American Brain Tumor Consortium trials 01-03 and 00-01 for recurrent or progressive malignant glioma. Experimental Design: EGFR expression and signaling during treatment with erlotinib or gefitinib were analyzed by Western blot and compared with pre–erlotinib/gefitinib–exposed tissue or unexposed controls. Tumors were also analyzed for EGFR mutations and for other genomic abnormalities by array-based comparative genomic hybridization. Clinical data were used to associate molecular features with tumor sensitivity to erlotinib or gefitinib. Results: Erlotinib and gefitinib did not markedly affect EGFR activity in vivo. No lung signature mutations of EGFR exons 18 to 21 were observed. There was no clear association between erlotinib/gefitinib sensitivity and deletion or amplification events on array-based comparative genomic hybridization analysis, although novel genomic changes were identified. Conclusions: As erlotinib and gefitinib were generally ineffective at markedly inhibiting EGFR phosphorylation in these tumors, other assays may be needed to detect molecular effects. Additionally, the mechanism of erlotinib/gefitinib sensitivity likely differs between brain and lung tumors. Finally, novel genomic changes, including deletions of chromosomes 6, 21, and 22, represent new targets for further research.
Humanized mice
Authors: Francesca Macchiarini, Markus G. Manz, A. Karolina Palucka, Leonard D. Shultz
Journal: The Journal of Experimental Medicine (2005)

Animal models have been instrumental in increasing the understanding of human physiology, particularly immunity. However, these animal models have been limited by practical considerations and genetic diversity. The creation of humanized mice that carry partial or complete human physiological systems may help overcome these obstacles. The National Institute of Allergy and Infectious Diseases convened a workshop on humanized mouse models for immunity in Bethesda, MD, on June 13–14, 2005, during which researchers discussed the benefits and limitations of existing animal models and offered insights into the development of future humanized mouse models.
Notch3 Is Critical for Proper Angiogenesis and Mural Cell Investment
Authors: Hua Liu, Wenbo Zhang, Simone Kennard, Ruth B. Caldwell, Brenda Lilly
Journal: Circulation Research (2010)

Rationale: The heterotypic interactions of endothelial cells and mural cells (smooth muscle cells or pericytes) are crucial for assembly, maturation, and subsequent function of blood vessels. Yet, the molecular mechanisms underlying their association have not been fully defined. Objective: Our previous in vitro studies indicated that Notch3, which is expressed in mural cells, mediates these cell–cell interactions. To assess the significance of Notch3 on blood vessel formation in vivo, we investigated its role in retinal angiogenesis. Methods and Results: We show that Notch3-deficient mice exhibit reduced retinal vascularization, with diminished sprouting and vascular branching. Moreover, Notch3 deletion impairs mural cell investment, resulting in progressive loss of vessel coverage. In an oxygen-induced retinopathy model, we demonstrate that Notch3 is induced in hypoxia and interestingly, pathological neovascularization is decreased in retinas of Notch3-null mice. Analysis of oxygen-induced retinopathy mediators revealed that angiopoietin-2 expression is significantly reduced in the absence of Notch3. Furthermore, in vitro experiments showed that Notch3 is sufficient for angiopoietin-2 induction, and this expression is additionally enhanced in the presence of hypoxia-inducible factor 1α. Conclusions: These results provide compelling evidence that Notch3 is important for the investment of mural cells and is a critical regulator of developmental and pathological blood vessel formation.
Association between Functional <i>EGF</i>+61 Polymorphism and Glioma Risk
Authors: Bruno Marques Costa, Paulo Ferreira, Sandra Costa, Paulo Canedo, Pedro Oliveira, Ana Silva, Fernando Pardal, Gianpaolo Suriano, José Carlos Machado, José Manuel Lopes, Rui Manuel Reis
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Epidermal growth factor (EGF) plays a critical role in cancer. A polymorphism in the EGF gene (EGF+61) may influence its expression and contribute to cancer predisposition and aggressiveness. In the present study, we aimed to elucidate the role of EGF+61 in glioma susceptibility and prognosis. Experimental Design: A case-control study involving 197 glioma patients and 570 controls was done. Univariate and multivariate logistic regression analyses were used to calculate odds ratio (OR) and 95% confidence intervals (95% CI). False-positive report probability was also assessed. The luciferase reporter gene assay was used to ascertain the functional consequences of this polymorphism. Results: Corroborating the univariate analysis, the multivariate model showed that the G allele conferred higher risks for gliomas (OR, 1.32; 95% CI, 1.04-1.67), glioblastomas (OR, 1.47; 95% CI, 1.02-2.10), and oligodendrogliomas (OR, 1.55; 95% CI, 1.07-2.23). The GG genotypes were associated with increased risk for gliomas (OR, 1.71; 95% CI, 1.07-2.73), glioblastomas (OR, 2.03; 95% CI, 1.02-4.05), and oligodendrogliomas (OR, 2.72; 95% CI, 1.18-6.28). In addition, the AG+GG genotypes were associated with higher risk for gliomas (OR, 1.52; 95% CI, 1.03-2.23) and oligodendrogliomas (OR, 2.80; 95% CI, 1.35-5.79). No significant association was observed between the EGF+61 polymorphism and glioblastoma or oligodendroglioma patients' overall survival. The luciferase reporter gene assay exhibited a significant increased promoter activity for the G variant compared with the reference A allele. Conclusions: These findings support the role of the EGF+61 polymorphism as a susceptibility factor for development of gliomas and show its implication on EGF promoter activity.
<i>miR-23a</i>, a Critical Regulator of “migR”ation and Metastasis in Colorectal Cancer
Authors: Zhiwei Wang, Wenyi Wei, Fazlul H. Sarkar
Journal: Cancer Discovery (2012)

Abstract Jahid and colleagues have shown that miR-23a promotes the transition from indolent to invasive colorectal cancer through inhibition of the MTSS1 tumor suppressor. This study reveals a novel role of miR-23a in the acceleration of colorectal cancer progression. Cancer Discov; 2(6); 489–91. ©2012 AACR Commentary on Jahid et al., p. 540.