tbuckley/cabot-search huggingface dataset:
FOXO3‐mTOR metabolic cooperation in the regulation of erythroid cell maturation and homeostasis
Authors: Xin Zhang, Genís Campreciós, Pauline Rimmelé, Raymond Liang, Safak Yalcin, Sathish Kumar Mungamuri, Jeffrey Barminko, Valentina D'Escamard, Margaret H. Baron, Carlo Brugnara, Dmitri Papatsenko, Stefano Rivella, Saghi Ghaffari
Journal: American Journal of Hematology (2014)

Ineffective erythropoiesis is observed in many erythroid disorders including β‐thalassemia and anemia of chronic disease in which increased production of erythroblasts that fail to mature exacerbate the underlying anemias. As loss of the transcription factor FOXO3 results in erythroblast abnormalities similar to the ones observed in ineffective erythropoiesis, we investigated the underlying mechanisms of the defective Foxo3 −/− erythroblast cell cycle and maturation. Here we show that loss of Foxo3 results in overactivation of the JAK2/AKT/mTOR signaling pathway in primary bone marrow erythroblasts partly mediated by redox modulation. We further show that hyperactivation of mTOR signaling interferes with cell cycle progression in Foxo3 mutant erythroblasts. Importantly, inhibition of mTOR signaling, in vivo or in vitro enhances significantly Foxo3 mutant erythroid cell maturation. Similarly, in vivo inhibition of mTOR remarkably improves erythroid cell maturation and anemia in a model of β‐thalassemia. Finally we show that FOXO3 and mTOR are likely part of a larger metabolic network in erythroblasts as together they control the expression of an array of metabolic genes some of which are implicated in erythroid disorders. These combined findings indicate that a metabolism‐mediated regulatory network centered by FOXO3 and mTOR control the balanced production and maturation of erythroid cells. They also highlight physiological interactions between these proteins in regulating erythroblast energy. Our results indicate that alteration in the function of this network might be implicated in the pathogenesis of ineffective erythropoiesis. Am. J. Hematol. 89:954–963, 2014. © 2014 Wiley Periodicals, Inc.
Induction in Rats of Paranasal Sinus Carcinomas With Radioactive Cerium Chloride2
Authors: J. R. Jasmin, C. Brocheriou, B. Klein, M. Morin, F. Smadja-Joffe, P. Cernea, C. Jasmin
Journal: JNCI Journal of the National Cancer Institute (1977)

A colloidal suspension of radioactive cerium stabilized in the form of hydroxide was inoculated into young Sprague-Dawley rats near the maxillary sinus. Well-differentiated epidermoid carcinomas of the paranasal sinus were obtained in 8 of 12 rats and in 8 of 9 animals that liver more then 200 days. Therefore, this istope was highly effectivein inducing tumors at the site of injection. The uniformity of the histologic type of tumors induced under these experimental conditions was remarkable.
Memory B cell development but not germinal center formation is impaired by in vivo blockade of CD40-CD40 ligand interaction.
Authors: D Gray, P Dullforce, S Jainandunsing
Journal: The Journal of Experimental Medicine (1994)

To study the role of the CD40-CD40 ligand interaction in the development of memory B cells and its level of action during primary antibody responses in vivo, mice were injected with a soluble CD40 fusion protein (sCD40-gamma 1), so as to block the interaction. The effects of the treatment on the primary antibody response were reminiscent of hyper-immunoglobulin M (IgM) syndrome (HIMG1): antigen-specific IgG responses were grossly inhibited whereas the IgM response was augmented severalfold. The latter observation suggests that there is a T-dependent, CD40 ligand-independent pathway of B cell activation that leads to IgM responses and that a significant component of the IgM in HIMG1 patients is derived from T-dependent responses. The secondary response was not readily blocked by sCD40-gamma 1 treatment, indicating a relative independence of CD40 ligation of antigen-experienced B cells. The most striking finding from these studies is that the development of memory B cell populations (measured by adoptive transfer) is grossly impaired by administration of sCD40-gamma 1 during the early induction phase of the response. It is surprising that although the generation memory is diminished, there is no quantitative difference in the development of germinal centers. Whereas entry of B cells into the memory cell pathway is dependent on CD40 ligation, the clonal expansion of the potential memory precursors in germinal centers seems not to require a CD40 signal.
Relations of Biomarkers Representing Distinct Biological Pathways to Left Ventricular Geometry
Authors: Raghava S. Velagaleti, Philimon Gona, Daniel Levy, Jayashri Aragam, Martin G. Larson, Geoffrey H. Tofler, Wolfgang Lieb, Thomas J. Wang, Emelia J. Benjamin, Ramachandran S. Vasan
Journal: Circulation (2008)

Background— Several biological pathways are activated concomitantly during left ventricular (LV) remodeling. However, the relative contribution of circulating biomarkers representing these distinct pathways to LV geometry is unclear. Methods and Results— We evaluated 2119 Framingham Offspring Study participants (mean age, 57 years; 57% women) who underwent measurements of biomarkers of inflammation (C-reactive protein), hemostasis (fibrinogen and plasminogen activator inhibitor-1), neurohormonal activation (B-type natriuretic peptide), and renin-angiotensin-aldosterone system (aldosterone and renin modeled as a ratio [ARR]) and echocardiography at a routine examination. LV geometry was defined on the basis of sex-specific distributions of LV mass (LVM) and relative wall thickness (RWT): normal (LVM and RWT &lt;80th percentile), concentric remodeling (LVM &lt;80th percentile but RWT ≥80th percentile), eccentric hypertrophy (LVM ≥80th percentile but RWT &lt;80th percentile), and concentric hypertrophy (LVM and RWT ≥80th percentile). We related the biomarker panel to LV geometry using polytomous logistic regression adjusting for clinical covariates and used backwards elimination to identify a parsimonious set of biomarkers associated with LV geometry. Modeled individually, C-reactive protein, fibrinogen, plasminogen activator inhibitor-1, and ARR were related to LV geometry ( P &lt;0.01). In multivariable analyses, the biomarker panel was significantly related to altered LV geometry ( P &lt;0.0001). On backwards elimination, logARR alone was significantly and positively associated with eccentric (odds ratio per SD increment, 1.20; 95% confidence interval, 1.05 to 1.37) and concentric LV hypertrophy (odds ratio per SD increment, 1.29; 95% confidence interval, 1.06 to 1.58). Conclusions— Our cross-sectional observations on a large community-based sample identified ARR as a key correlate of concentric and eccentric LV hypertrophy, consistent with a major role for the renin-angiotensin-aldosterone system in LV remodeling.
Defibrillation and cardioversion
Authors: B Lown
Journal: Cardiovascular Research (2002)

Going back to the ‘archaic past and to obsolete ancestors’ [1] provides insight not only where we came from but where we might be heading. Indeed history matters in medicine as it does in everyday life. It is now 40 years since the introduction of DC defibrillation and cardioversion [2,3]. Like the proverbial pebble cast in the water, the ripple effects of these technologies extend beyond the horizon of early prediction. Among the more important consequences were: stimulating the development of coronary care units, facilitating the emergence of coronary bypass and other heart operations, focusing attention on the still formidable out-of-hospital problem of sudden cardiac death, advancing the field of clinical electrophysiology and contributing to implantable devices to protect against death from malignant arrhythmias. Most important are the countless lives saved with this straightforward medical advance.

From time immemorial, drugs, potions and herbs were the mainstay in treating arrhythmias of the heart. This therapeutic approach presented formidable limitations. In the individual patient the effective dose of the drug was unknown. A tedious biological titration was required to avoid serious or even life threatening toxic reactions. When the arrhythmia was ventricular tachycardia, the route for administering drugs was necessarily intravenous, thereby maximizing the likelihood of adverse reactions. When drugs were given orally, the required incremental dosing consumed hours and at times days. Even with the most scrupulous monitoring, toxic reactions were nearly unavoidable.

Looking back it is remarkable how the clinical topography has changed since the introduction of DC defibrillation and cardioversion. One example may be illustrative. Levine, during 33 years of clinical practice, observed only 137 episodes in 107 cases of paroxysmal ventricular tachycardia [4]. This represents approximately three patients annually; it may be far less, since all wide complex tachycardias were designated as ventricular. In contrast during …
Differential Toxicity of Nuclear RNA Foci versus Dipeptide Repeat Proteins in a Drosophila Model of C9ORF72 FTD/ALS
Authors: Helene Tran, Sandra Almeida, Jill Moore, Tania F. Gendron, UmaDevi Chalasani, Yubing Lu, Xing Du, Jeffrey A. Nickerson, Leonard Petrucelli, Zhiping Weng, Fen-Biao Gao
Journal: Neuron (2015)
Protein Kinase C Enzymes in the Hematopoietic and Immune Systems
Authors: Amnon Altman, Kok-Fai Kong
Journal: Annual Review of Immunology (2016)

The protein kinase C (PKC) family, discovered in the late 1970s, is composed of at least 10 serine/threonine kinases, divided into three groups based on their molecular architecture and cofactor requirements. PKC enzymes have been conserved throughout evolution and are expressed in virtually all cell types; they represent critical signal transducers regulating cell activation, differentiation, proliferation, death, and effector functions. PKC family members play important roles in a diverse array of hematopoietic and immune responses. This review covers the discovery and history of this enzyme family, discusses the roles of PKC enzymes in the development and effector functions of major hematopoietic and immune cell types, and points out gaps in our knowledge, which should ignite interest and further exploration, ultimately leading to better understanding of this enzyme family and, above all, its role in the many facets of the immune system.
Acute markers of neutrophilic lung infiltration in the non-human primate LPS model
Authors: Stephen Jordan, Erroll Spridgen, Virgina Fisher, Jennifer Hincks, Tony Grasiewicz, Ken Meecham
Journal: European Respiratory Journal (2014)

The non-human primate LPS model bridges the translation between pre-clinical rodent and LPS proof of concept studies in healthy volunteers. The response to LPS in the primate is documented at 24h and beyond but less data is available at earlier time points generally utilised in endotoxin exposure studies in man.  The aim of this study was to determine whether the temporal inflammatory response at 6 and 24h following LPS exposure in the cynomologus monkey was similar to man and that observed in rodent studies. The study also evaluated the efficacy of an oral glucocorticoid against measures of pulmonary inflammation.  Four primates in a cross over design, underwent a recovery segmental bronchoalveolar Lavage (BAL) pre-treatment, 6 and 24h following aerosolised LPS exposure. Two animals were administered vehicle and two dexamethasone by oral gavage 1h prior and 7h post LPS exposure. Exposure to LPS produced a significant (p  The rapid increase in soluble markers and neutrophilic lung infiltration measured in healthy volunteers and rodents is replicated in early time points following LPS exposure in the steroid sensitive non-human primate model.
Identification of a Stat3-Dependent Transcription Regulatory Network Involved in Metastatic Progression
Authors: Jill J. Ranger, David E. Levy, Solmaz Shahalizadeh, Michael Hallett, William J. Muller
Journal: Cancer Research (2009)

Abstract High levels of activated Stat3 are often found in human breast cancers and can correlate with poor patient outcome. We employed an activated ErbB2 mouse model of breast cancer to investigate the in vivo role of Stat3 in mammary tumor progression and found that Stat3 does not alter mammary tumor initiation but dramatically affects metastatic progression. Four-fold fewer animals exhibited lung metastases in the absence of Stat3 and a 12-fold reduction in the number of lung lesions was observed in animals bearing Stat3-null tumors when compared with the wild-type cohort. The decreased malignancy in Stat3-deficient tumors is attributed to a reduction in both angiogenic and inflammatory responses associated with a Stat3-dependent transcriptional cascade involving CCAAT/enhancer binding protein δ. [Cancer Res 2009;69(17):6823–30]
The Decline in Blood Glucose Levels Is Less With Intermittent High-Intensity Compared With Moderate Exercise in Individuals With Type 1 Diabetes
Authors: Kym J. Guelfi, Timothy W. Jones, Paul A. Fournier
Journal: Diabetes Care (2005)

OBJECTIVE—To compare the response of blood glucose levels to intermittent high-intensity exercise (IHE) and moderate-intensity exercise (MOD) in individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS—Seven healthy individuals with type 1 diabetes were tested on two separate occasions, during which either a 30-min MOD or IHE protocol was performed. MOD consisted of continuous exercise at 40% Vo2peak, while the IHE protocol involved a combination of continuous exercise at 40% Vo2peak interspersed with 4-s sprints performed every 2 min to simulate the activity patterns of team sports. RESULTS—Both exercise protocols resulted in a decline in blood glucose levels. However, the decline was greater with MOD (−4.4 ± 1.2 mmol/l) compared with IHE (−2.9 ± 0.8 mmol/l; P &amp;lt; 0.05), despite the performance of a greater amount of total work with IHE (P &amp;lt; 0.05). During 60 min of recovery from exercise, glucose levels remained higher in IHE compared with MOD (P &amp;lt; 0.05). Furthermore, glucose levels remained stable during recovery from IHE, while they continued to decrease after MOD (P &amp;lt; 0.05). The stabilization of blood glucose levels with IHE was associated with elevated levels of lactate, catecholamines, and growth hormone during early recovery from exercise (P &amp;lt; 0.05). There were no differences in free insulin, glucagon, cortisol, or free fatty acids between MOD and IHE. CONCLUSIONS—The decline in blood glucose levels is less with IHE compared with MOD during both exercise and recovery in individuals with type 1 diabetes.
microRNA: A Master Regulator of Cellular Processes for Bioengineering Systems
Authors: Wei Sun, Yi-Shuan Julie Li, Hsien-Da Huang, John Y-J. Shyy, Shu Chien
Journal: Annual Review of Biomedical Engineering (2010)

microRNAs (miRNAs) are small RNAs 18 to 24 nucleotides in length that serve the pivotal function of regulating gene expression. Instead of being translated into proteins, the mature single-stranded miRNA binds to messenger RNAs (mRNAs) to interfere with the translational process. It is estimated that whereas only 1% of the genomic transcripts in mammalian cells encode miRNA, nearly one-third of the encoded genes are regulated by miRNA. Various bioinformatics databases, tools, and algorithms have been developed to predict the sequences of miRNAs and their target genes. In combination with the in silico approaches in systems biology, experimental studies on miRNA provide a new bioengineering approach for understanding the mechanism of fine-tuning gene regulation. This review aims to provide state-of-the-art information on this important mechanism of gene regulation for researchers working in biomedical engineering and related fields. Particular emphases are placed on summarizing the current tools and strategies for miRNA study from a bioengineering perspective and the possible applications of miRNAs (such as antagomirs and miRNA sponges) in biomedical engineering research.
Aloperine executes antitumor effects against multiple myeloma through dual apoptotic mechanisms
Authors: He Wang, Shu Yang, Hong Zhou, Mingna Sun, Lingran Du, Minyan Wei, Meixia Luo, Jingzhu Huang, Hongzhu Deng, Yinghong Feng, Jun Huang, Yi Zhou
Journal: Journal of Hematology & Oncology (2015)

Aloperine, a natural alkaloid constituent isolated from the herb Sophora alopecuroides displays anti-inflammatory properties in vitro and in vivo. Our group previously demonstrated that aloperine significantly induced apoptosis in colon cancer SW480 and HCT116 cells. However, its specific target(s) remain to be discovered in multiple myeloma (MM) and have not been investigated.Human myeloma cell lines (n = 8), primary myeloma cells (n = 12), drug-resistant myeloma cell lines (n = 2), and animal models were tested for their sensitivity to aloperine in terms of proliferation and apoptosis both in vitro and in vivo, respectively. We also examined the functional mechanisms underlying the apoptotic pathways triggered by aloperine.Aloperine induced MM cell death in a dose- and time-dependent manner, even in the presence of the proliferative cytokines interleukin-6 and insulin-like growth factor I. Mechanistic studies revealed that aloperine not only activated caspase-8 and reduced the expression of FADD-like interleukin-1β-converting enzyme (FLICE)-like inhibitory protein long (FLIPL) and FLICE-inhibitory proteins (FLIPS) but also activated caspase-9 and decreased the expression of phosphorylated (p)-PTEN. Moreover, co-activation of the caspase-8/cellular FLICE-inhibitory protein (cFLIP)- and caspase-9/p-PTEN/p-AKT-dependent apoptotic pathways by aloperine caused irreversible inhibition of clonogenic survival. Aloperine induce more MM apoptosis with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or borterzomib. A U266 xenograft tumor model and 5T33 MM cells recapitulated the antitumor efficacy of aloperine, and the animals displayed excellent tolerance of the drug and few adverse effects.Aloperine has multifaceted antitumor effects on MM cells. Our data support the clinical development of aloperine for MM therapy.
Clinical investigation of athletes with persistent fatigue and/or recurrent infections
Authors: V L Reid, M Gleeson, N Williams, R L Clancy
Journal: British Journal of Sports Medicine (2004)

To investigate whether underlying medical conditions contribute to the fatigue and high incidence of infections that can occur during repeated intense training.Forty one competitive athletes (22 male, 19 female) with persistent fatigue and/or recurrent infections associated with performance decrements had a thorough medical examination and a series of clinical investigations to identify potential medical causes.Conditions with the potential to cause fatigue and/or recurrent infections were identified in 68% of the athletes. The most common were partial humoral immune deficiency (28%) and unresolved viral infections (27%). Non-fasting hypoglycaemia was common (28%). Other conditions included allergic disease (15%), new or poorly controlled asthma (13%), upper airway dysfunction (5%), sleep disorders (15%), iron depletion (3%), and one case of a thyroid disorder. A positive antinuclear antibody was detected in 21% of the athletes, without any clinical evidence of autoimmune disorders. Evidence of Epstein-Barr virus reactivation was detected in 22% of the athletes tested.Athletes with recurrent infections, fatigue, and associated poor performance may benefit from a thorough investigation of potentially reversible underlying medical conditions, especially when these conditions cause disruption to training and competition. Unresolved viral infections are not routinely assessed in elite athletes, but it may be worth considering in those experiencing fatigue and performing poorly.
Automated quantitative analysis of DCC tumor suppressor protein in ovarian cancer tissue microarray shows association with β-catenin levels and outcome in patients with epithelial ovarian cancer
Authors: A. Bamias, Z. Yu, P.M. Weinberger, S. Markakis, D. Kowalski, R.L. Camp, D.L. Rimm, M.A. Dimopoulos, A. Psyrri
Journal: Annals of Oncology (2006)
Tidal volume, recruitment and compliance in HFOV: same principles, different frequency: Figure 1–
Authors: J. Jane Pillow
Journal: European Respiratory Journal (2012)

The widespread clinical introduction of high-frequency oscillatory ventilation (HFOV) for the treatment of respiratory distress syndrome in neonates in the late 1980s and early 1990s heralded a new era of understanding of the optimal approach to lung volume ( V L) recruitment, which embraced the concept of open lung ventilation [1]. The promotion of HFOV as a means of independently controlling oxygenation and ventilation contributed to the ease with which it was accepted as a clinical treatment in many neonatal units. Unlike mechanical ventilation at physiological breathing rates where changes in ventilator settings on contemporary ventilators inevitably affect both oxygenation and ventilation, traditional teaching of HFOV promoted changes in mean airway pressure as the means of influencing arterial oxygen tension and alterations to proximal pressure amplitude (Δ P ) and frequency ( f ) of the oscillatory waveform as the determinants of arterial carbon dioxide tension ( P a,CO2) [2]. Like any intensive care technology, however, successful and safe application of HFOV is highly dependent on fully understanding the specific nuances of this ventilatory modality.

As recognised previously, there are clear changes in compliance during recruitment of the atelectatic lung [3]. During ventilation at conventional breathing rates, as V L is recruited, lung compliance improves and this is accompanied by increased tidal volume ( V T) to which the clinical response is normally a reduction in minute volume: in synchronised modes, this is most often achieved via a reduction in Δ P or targeted V T rather than a reduction in respiratory rate.

Changes in compliance [4–7] and lung tissue resistance [5] have also been widely recognised during volume recruitment achieved with HFOV. In this issue of the European Respiratory Journal , Miedema et al. [8] present an elegant study …
Expression and distribution of brain natriuretic peptide in human right atria
Authors: Kiyoshi Doyama, Manabu Fukumoto, Genzou Takemura, Masaru Tanaka, Teiji Oda, Koji Hasegawa, Tsukasa Inada, Seiji Ohtani, Takako Fujiwara, Hiroshi Itoh, Kazuwa Nakao, Shigetake Sasayama, Hisayoshi Fujiwara
Journal: Journal of the American College of Cardiology (1998)
Identification of co-regulated transcripts affecting male body size in Drosophila.
Authors: Cynthia J Coffman, Marta L Wayne, Sergey V Nuzhdin, Laura A Higgins, Lauren M McIntyre
Journal: Genome biology (2005)

Factor analysis is an analytic approach that describes the covariation among a set of genes through the estimation of 'factors', which may be, for example, transcription factors, microRNAs (miRNAs), and so on, by which the genes are co-regulated. Factor analysis gives a direct mechanism by which to relate gene networks to complex traits. Using simulated data, we found that factor analysis clearly identifies the number and structure of factors and outperforms hierarchical cluster analysis. Noise genes, genes that are not correlated with any factor, can be distinguished even when factor structure is complex. Applied to body size in Drosophila simulans, an evolutionarily important complex trait, a factor was directly associated with body size.