tbuckley/cabot-search huggingface dataset:
Echocardiography Screening for Rheumatic Heart Disease in Ugandan Schoolchildren
Authors: Andrea Beaton, Emmy Okello, Peter Lwabi, Charles Mondo, Robert McCarter, Craig Sable
Journal: Circulation (2012)

Historically, sub-Saharan Africa has had the highest prevalence rates of clinically detected rheumatic heart disease (RHD). Echocardiography-based screening improves detection of RHD in endemic regions. The newest screening guidelines (2006 World Health Organization/National Institutes of Health) have been tested across India and the Pacific Islands, but application in sub-Saharan Africa has, thus far, been limited to Mozambique. We used these guidelines to determine RHD prevalence in a large cohort of Ugandan school children, to identify risk factors for occult disease, and to assess the value of laboratory testing.Auscultation and portable echocardiography were used to screen randomly selected schoolchildren, 5 to 16 years of age, in Kampala, Uganda. Disease likelihood was defined as definite, probable, or possible in accordance with the 2006 National Institutes of Health/World Health Organization guidelines. Ninety-seven percent of eligible students received screening (4869 of 5006). Among them, 130 children (2.7%) had abnormal screening echocardiograms. Of those 130, secondary evaluation showed 72 (55.4%) with possible, probable, or definite RHD; 18 (13.8%) with congenital heart disease; and 40 (30.8%) with no disease. Echocardiography detected 3 times as many cases of RHD as auscultation: 72 (1.5%) versus 23 (0.5%; P<0.001). Children with RHD were older (10.1 versus 9.3 years; P=0.002). Most cases (98%) involved only the mitral valve. Lower socioeconomic groups had more RHD (2.7% versus 1.4%; P=0.036) and more advanced disease (64% versus 26%; P<0.001). Antistreptolysin O titers were elevated in children with definite RHD.This is one of the largest single-country childhood RHD prevalence studies and the first to be conducted in sub-Saharan Africa. Our data support inclusion of echocardiography in screening protocols, even in the most resource-constrained settings, and identify lower socioeconomic groups as most vulnerable. Longitudinal follow-up of children with echocardiographically diagnosed subclinical RHD is needed.
Effects of pulmonary function of whole lung irradiation for Wilm's tumour in children.
Authors: M R Benoist, J Lemerle, R Jean, P Rufin, P Scheinmann, J Paupe
Journal: Thorax (1982)

The effect of whole lung irradiation on lung function was investigated in 48 children treated for Wilm's tumour with pulmonary metastases. Lung function tests were performed before irradiation and were repeated annually for as long as possible, the length of follow-up varying from two to 17 years. A reduction in both lung volume and in dynamic compliance was clearly observed. In some patients these changes occurred in the early post-irradiation months, but in most the decrease observed progressed over longer periods of time. Static pressure volume curves, blood-gases, and carbon monoxide transfer were normal. These findings make it unlikely that post-irradiation pulmonary fibrosis was involved. Another explanation for the decreased lung volume and dynamic compliance might be failure of alveolar multiplication. Muscular injury is unlikely as the patients were able to produce normal transthoracic pressures. A failure of chest wall growth is also possible and would explain the progressive restrictive impairment but not the early lung function changes. It is suggested that the early effects detected in some patients were the result of lung injury and that later effects resulted from impaired chest wall growth.
Acid-Mediated Tumor Invasion: a Multidisciplinary Study
Authors: Robert A. Gatenby, Edward T. Gawlinski, Arthur F. Gmitro, Brant Kaylor, Robert J. Gillies
Journal: Cancer Research (2006)

Abstract The acid-mediated tumor invasion hypothesis proposes altered glucose metabolism and increased glucose uptake, observed in the vast majority of clinical cancers by fluorodeoxyglucose-positron emission tomography, are critical for development of the invasive phenotype. In this model, increased acid production due to altered glucose metabolism serves as a key intermediate by producing H+ flow along concentration gradients into adjacent normal tissue. This chronic exposure of peritumoral normal tissue to an acidic microenvironment produces toxicity by: (a) normal cell death caused by the collapse of the transmembrane H+ gradient inducing necrosis or apoptosis and (b) extracellular matrix degradation through the release of cathepsin B and other proteolytic enzymes. Tumor cells evolve resistance to acid-induced toxicity during carcinogenesis, allowing them to survive and proliferate in low pH microenvironments. This permits them to invade the damaged adjacent normal tissue despite the acid gradients. Here, we describe theoretical and empirical evidence for acid-mediated invasion. In silico simulations using mathematical models provide testable predictions concerning the morphology and cellular and extracellular dynamics at the tumor-host interface. In vivo experiments confirm the presence of peritumoral acid gradients as well as cellular toxicity and extracellular matrix degradation in the normal tissue exposed to the acidic microenvironment. The acid-mediated tumor invasion model provides a simple mechanism linking altered glucose metabolism with the ability of tumor cells to form invasive cancers. (Cancer Res 2006; 66(10): 5216-23)
Sequential Inhibitor Therapy in CML: <i>In Vitro</i> Simulation Elucidates the Pattern of Resistance Mutations after Second- and Third-Line Treatment
Authors: Robert C. Bauer, Jana Sänger, Christian Peschel, Justus Duyster, Nikolas von Bubnoff
Journal: Clinical Cancer Research (2013)

Dasatinib and nilotinib are active in imatinib-resistant chronic myelocytic leukemia (CML) and many patients undergo sequential treatment. We aimed at modeling sequential tyrosine kinase inhibitor (TKI) resistance in vitro to compare the sequences imatinib-nilotinib-dasatinib and imatinib-dasatinib-nilotinib.We designed an in vitro model for sequential TKI resistance in CML. Replicates of imatinib-resistant cell lines were treated with dasatinib or nilotinib. Second-line resistant replicates were exposed to third-line treatment.Growth of all replicates in all three lines of treatment was associated with T315I. However, T315I occurred with low abundance and did not increase during sequential treatment. Nilotinib second-line more often gave rise to sequential resistance compared with dasatinib due to pre-existing P-loop mutations, especially at suboptimal drug concentration. In contrast, mutations predisposing to dasatinib resistance such as F317C/V and V299L did not occur before dasatinib exposure. Nilotinib third-line did not overcome imatinib-dasatinib resistance due to pre-existing T315I or P-loop/V299L or P-loop/F317 exchanges. Dasatinib third-line suppressed imatinib-nilotinib-resistant replicates with residual sensitivity.Sequential acquisition of BCR-ABL drug resistance mutations in CML might be underestimated. Resistance to sequential TKI monotherapy in vitro more often was associated with stepwise acquisition of drug-specific compound mutations compared with T315I. Pre-existing mutations strongly limited the activity of both third-line treatments, and the activity of nilotinib second-line in vitro critically depended on drug concentration.
Influence of hyperkalaemia and ischaemia on non-receptor-mediated cardiac electrophysiological effects of naloxone
Authors: K. G Oldroyd, M. N Hicks, S. M Cobbe
Journal: Cardiovascular Research (1993)

The aim was to investigate the cardiac electrophysiological effects of the opioid receptor antagonist naloxone and examine whether hyperkalaemia and ischaemia influence these effects.The cardiac electrophysiological effects of racemic naloxone, nalmafene, and morphine were examined in superfused rabbit papillary muscles under normal conditions and in the case of naloxone under conditions of hyperkalaemia. The electrophysiological effects of racemic naloxone and d-naloxone were examined in arterially perfused rabbit interventricular septa before and during 30 min global zero flow ischaemia; the rate of rise of extracellular K+ concentration was also measured.Naloxone, nalmafene and morphine all prolonged action potential duration and effective refractory period in superfused papillary muscles (class III effects), suggesting that these effects are not receptor mediated. During hyperkalaemia, naloxone increased the depressant effect on the maximum upstroke velocity of the action potential and enhanced post-repolarisation refractoriness, further suggesting a class I effect. Both racemic naloxone (active at opioid receptors) and d-naloxone (inactive) prolonged action potential duration and effective refractory period in septa, again suggesting non-receptor-mediated effects. During myocardial ischaemia the class III effects of both compounds were gradually lost in such a way that post-repolarisation refractoriness developed. Both compounds reduced the rate of rise of extracellular K+ concentration and preserved resting membrane potential, but the fall in maximum upstroke velocity was enhanced, again suggesting that naloxone has an additional class I effect in partially depolarised ventricular myocardium.The antiarrhythmic activity of naloxone in models of myocardial ischaemia/reperfusion can be explained by non-opioid receptor mediated effects on the duration and maximum upstroke velocity of the action potential and on extracellular potassium accumulation during ischaemia.
Failure of demand pacing with small surface area electrodes.
Authors: H C Hughes, R R Brownlee, G F Tyers
Journal: Circulation (1976)

As pacemaker electrode myocardial contact area is reduced, the energy required to stimulate the heart decreases; but the effect of surface area on an electrode's ability to transmit R-wave potentials has not been well documented. Endocardial and intramyocardial R-wave potentials were measured in ten dogs with seven commercially available pacemaker electrodes of different surface area. With a load impedance of 1000 ohms, there was a direct correlation between surface area and the R-wave potentials measured. The amplitude of the R-wave that resulted from conduction from the heart to the sensor via the electrode system decreased with decreasing surface area. A similar direct correlation was seen between the R-wave potentials measured and the threshold current and energy requirements. With the present trend toward utilization of small surface area electrodes to reduce pacemaker cell drain, care must be taken to optimize pacemaker circuit impedance if sensing problems are to be avoided.
Response to Neoadjuvant Therapy and Long-Term Survival in Patients With Triple-Negative Breast Cancer
Authors: Cornelia Liedtke, Chafika Mazouni, Kenneth R. Hess, Fabrice André, Attila Tordai, Jaime A. Mejia, W. Fraser Symmans, Ana M. Gonzalez-Angulo, Bryan Hennessy, Marjorie Green, Massimo Cristofanilli, Gabriel N. Hortobagyi, Lajos Pusztai
Journal: Journal of Clinical Oncology (2008)

Purpose Triple-negative breast cancer (TNBC) is defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression. In this study, we compared response to neoadjuvant chemotherapy and survival between patients with TNBC and non-TNBC. Patients and Methods Analysis of a prospectively collected clinical database was performed. We included 1,118 patients who received neoadjuvant chemotherapy at M.D. Anderson Cancer Center for stage I-III breast cancer from 1985 to 2004 and for whom complete receptor information were available. Clinical and pathologic parameters, pathologic complete response rates (pCR), survival measurements, and organ-specific relapse rates were compared between patients with TNBC and non-TNBC. Results Two hundred fifty-five patients (23%) had TNBC. Patients with TNBC compared with non-TNBC had significantly higher pCR rates (22% v 11%; P = .034), but decreased 3-year progression-free survival rates (P &lt; .0001) and 3-year overall survival (OS) rates (P &lt; .0001). TNBC was associated with increased risk for visceral metastases (P = .0005), lower risk for bone recurrence (P = .027), and shorter postrecurrence survival (P &lt; .0001). Recurrence and death rates were higher for TNBC only in the first 3 years. If pCR was achieved, patients with TNBC and non-TNBC had similar survival (P = .24). In contrast, patients with residual disease (RD) had worse OS if they had TNBC compared with non-TNBC (P &lt; .0001). Conclusion Patients with TNBC have increased pCR rates compared with non-TNBC, and those with pCR have excellent survival. However, patients with RD after neoadjuvant chemotherapy have significantly worse survival if they have TNBC compared with non-TNBC, particularly in the first 3 years.
Cytolytic activity of purified cytoplasmic granules from cytotoxic rat large granular lymphocyte tumors.
Authors: P A Henkart, P J Millard, C W Reynolds, M P Henkart
Journal: The Journal of Experimental Medicine (1984)

Purified cytoplasmic granules from cytotoxic rat large granular lymphocytes (LGL) tumors were cytolytic to erythrocytes, splenocytes, and a number of different lymphoid tumor cells. Granule concentrations of approximately 1 microgram/ml granule protein were adequate to lyse 100% of the erythrocytes, while the nucleated cells required up to 100 micrograms/ml granule protein to achieve complete lysis. Cytoplasmic granules purified from noncytotoxic lymphoid cells did not contain detectable cytolytic activity; purified granules from rat mast cells and rat liver lysosomes likewise failed to display cytolytic activity. However, granules prepared from normal rat peripheral blood LGL were cytolytic. Granule-mediated lysis of erythrocytes and nucleated cells was complete within 3 min at room temperature. The lytic activity required calcium at concentrations of 10(-4)-10(-2) M; magnesium or barium failed to replace calcium, while strontium could replace calcium at 10(-3)-10(-2) M when nucleated cells were the target. Exposure of LGL tumor granules to calcium before the addition of target cells resulted in an inactivation of granule cytolytic activity over the course of 20 min at room temperature. Granule cytolytic activity was heat and Pronase sensitive, and could be solubilized by 2 M salt. Examination of granules exposed to calcium in the electron microscope using negative staining showed that calcium treatment of granules results in the formation of ring-shaped structures previously described to be associated with LGL-mediated cytotoxicity. These results provide support for the hypothesis that the cytotoxic processes mediated by LGL are a secretory event characterized by the release of cytolytic material from the cytoplasmic granules after triggering by a surface receptor. The results further suggest that the ring structures visible in the electron microscope are associated with the lytic event.
Antiinflammatory properties of hepatic acute phase proteins: preferential induction of interleukin 1 (IL-1) receptor antagonist over IL-1 beta synthesis by human peripheral blood mononuclear cells.
Authors: H Tilg, E Vannier, G Vachino, C A Dinarello, J W Mier
Journal: The Journal of Experimental Medicine (1993)

This study was undertaken to determine whether acute phase proteins (APP) induce the synthesis of interleukin 1 beta (IL-1 beta) and its specific antagonist, IL-1 receptor antagonist (IL-1Ra), in human peripheral blood mononuclear cells (PBMC). PBMC from healthy volunteers were incubated with C-reactive protein (CRP), alpha 1-antitrypsin (alpha 1-AT), or alpha 1-acid glycoprotein (AGP), and the levels of IL-1 beta and IL-1Ra produced were measured by specific radioimmunoassay. To evaluate the effects of alpha 1-AT further, a synthetic pentapeptide FVYLI corresponding to the minimal binding sequence for the serpine-enzyme complex receptor was also evaluated. PBMC incubated for 24 h with CRP, alpha 1-AT, or the pentapeptide FVYLI synthesized large quantities of IL-1Ra, 5-10-fold greater than the amount of IL-1 beta produced by these cells. AGP induced significantly less IL-1Ra than the other APP tested. These effects were shown to be specific, in that polyclonal antibodies against CRP, alpha 1-AT, and AGP eliminated the cytokine production induced by these respective proteins. CRP, alpha 1-AT, FVYLI, and AGP were synergistic with low concentrations of endotoxin in the induction of both IL-1Ra and IL-1 beta synthesis. We suggest that the preferential induction of IL-1Ra by APP may contribute to their antiinflammatory effects and provide an important regulatory signal for the acute phase response.
Feasibility Trial of Letrozole in Combination With Bevacizumab in Patients With Metastatic Breast Cancer
Authors: Tiffany A. Traina, Hope S. Rugo, James F. Caravelli, Sujata Patil, Benjamin Yeh, Michele E. Melisko, John W. Park, Stephanie Geneus, Matthew Paulson, Jill Grothusen, Andrew D. Seidman, Monica Fornier, Diana Lake, Chau Dang, Mark Robson, Maria Theodoulou, Carlos D. Flombaum, Larry Norton, Clifford A. Hudis, Maura N. Dickler
Journal: Journal of Clinical Oncology (2009)

Preclinical models suggest that the use of anti-vascular endothelial growth factor (anti-VEGF) therapy with antiestrogens may prevent or delay the development of endocrine therapy resistance. We therefore performed a feasibility study to evaluate the safety of letrozole plus bevacizumab in patients with hormone receptor-positive metastatic breast cancer (MBC).
Very Little Intron Gain in Entamoeba histolytica Genes Laterally Transferred from Prokaryotes
Authors: Scott William Roy, Manuel Irimia, David Penny
Journal: Molecular Biology and Evolution (2006)

The evolution of spliceosomal introns remains intensely debated. We studied 96 Entamoeba histolytica genes previously identified as having been laterally transferred from prokaryotes, which were presumably intronless at the time of transfer. Ninety out of the 96 are also present in the reptile parasite Entamoeba invadens, indicating lateral transfer before the species' divergence ∼50 MYA. We find only 2 introns, both shared with E. invadens. Thus, no intron gains have occurred in ∼50 Myr, implying a very low rate of intron gain of less than one gain per gene per ∼4.5 billion years. Nine other predicted introns are due to annotation errors reflecting apparent mistakes in the E. histolytica genome assembly. These results underscore the massive differences in intron gain rates through evolution.
Vaccination of immunocompromised patients
Authors: Per Ljungman
Journal: Clinical Microbiology and Infection (2012)

Vaccination of immunocompromised patients is challenging both regarding efficacy and safety. True efficacy data are lacking so existing recommendations are based on immune responses and safety data. Inactivated vaccines can generally be used without risk but the patients who are most at risk for infectious morbidity and mortality as a result of their severely immunosuppressed state are also those least likely to respond to vaccination. However, vaccination against pneumococci, Haemophilus influenzae and influenza are generally recommended. Live vaccines must be used with care because the risk for vaccine-associated disease exists.
Ring finger protein20 regulates hepatic lipid metabolism through protein kinase A-dependent sterol regulatory element binding protein1c degradation
Authors: Jae Ho Lee, Gha Young Lee, Hagoon Jang, Sung Sik Choe, Seung-Hoi Koo, Jae Bum Kim
Journal: Hepatology (2014)

Sterol regulatory element binding protein1c (SREBP1c) is a key transcription factor for de novo lipogenesis during the postprandial state. During nutritional deprivation, hepatic SREBP1c is rapidly suppressed by fasting signals to prevent lipogenic pathways. However, the molecular mechanisms that control SREBP1c turnover in response to fasting status are not thoroughly understood. To elucidate which factors are involved in the inactivation of SREBP1c, we attempted to identify SREBP1c-interacting proteins by mass spectrometry analysis. Since we observed that ring finger protein20 (RNF20) ubiquitin ligase was identified as one of SREBP1c-interacting proteins, we hypothesized that fasting signaling would promote SREBP1c degradation in an RNF20-dependent manner. In this work, we demonstrate that RNF20 physically interacts with SREBP1c, leading to degradation of SREBP1c via ubiquitination. In accordance with these findings, RNF20 represses the transcriptional activity of SREBP1c and turns off the expression of lipogenic genes that are targets of SREBP1c. In contrast, knockdown of RNF20 stimulates the expression of SREBP1c and lipogenic genes and induces lipogenic activity in primary hepatocytes. Furthermore, activation of protein kinase A (PKA) with glucagon or forskolin enhances the expression of RNF20 and potentiates the ubiquitination of SREBP1c via RNF20. In wild-type and db/db mice, adenoviral overexpression of RNF20 markedly suppresses FASN promoter activity and reduces the level of hepatic triglycerides, accompanied by a decrease in the hepatic lipogenic program. Here, we reveal that RNF20-induced SREBP1c ubiquitination down-regulates hepatic lipogenic activity upon PKA activation. Conclusion : RNF20 acts as a negative regulator of hepatic fatty acid metabolism through degradation of SREBP1c upon PKA activation. Knowledge regarding this process enhances our understanding of how SREBP1c is able to turn off hepatic lipid metabolism during nutritional deprivation. (Hepatology 2014;60:844–857)
Consumption of fish and meats and risk of hepatocellular carcinoma: the European Prospective Investigation into Cancer and Nutrition (EPIC)
Authors: V. Fedirko, A. Trichopolou, C. Bamia, T. Duarte-Salles, E. Trepo, K. Aleksandrova, U. Nöthlings, A. Lukanova, P. Lagiou, P. Boffetta, D. Trichopoulos, V.A. Katzke, K. Overvad, A. Tjønneland, L. Hansen, M.C. Boutron-Ruault, G. Fagherazzi, N. Bastide, S. Panico, S. Grioni, P. Vineis, D. Palli, R. Tumino, H.B. Bueno-de-Mesquita, P.H. Peeters, G. Skeie, D. Engeset, C.L. Parr, P. Jakszyn, M.J. Sánchez, A. Barricarte, P. Amiano, M. Chirlaque, J.R. Quirós, M. Sund, M. Werner, E. Sonestedt, U. Ericson, T.J. Key, K.T. Khaw, P. Ferrari, I. Romieu, E. Riboli, M. Jenab
Journal: Annals of Oncology (2013)
The intramembrane protease SPPL2a promotes B cell development and controls endosomal traffic by cleavage of the invariant chain
Authors: Janna Schneppenheim, Ralf Dressel, Susann Hüttl, Renate Lüllmann-Rauch, Michael Engelke, Kai Dittmann, Jürgen Wienands, Eeva-Liisa Eskelinen, Irm Hermans-Borgmeyer, Regina Fluhrer, Paul Saftig, Bernd Schröder
Journal: The Journal of Experimental Medicine (2012)

Regulated intramembrane proteolysis is a central cellular process involved in signal transduction and membrane protein turnover. The presenilin homologue signal-peptide-peptidase-like 2a (SPPL2a) has been implicated in the cleavage of type 2 transmembrane proteins. We show that the invariant chain (li, CD74) of the major histocompatability class II complex (MHCII) undergoes intramembrane proteolysis mediated by SPPL2a. B lymphocytes of SPPL2a−/− mice accumulate an N-terminal fragment (NTF) of CD74, which severely impairs membrane traffic within the endocytic system and leads to an altered response to B cell receptor stimulation, reduced BAFF-R surface expression, and accumulation of MHCII in transitional developmental stage T1 B cells. This results in significant loss of B cell subsets beyond the T1 stage and disrupted humoral immune responses, which can be recovered by additional ablation of CD74. Hence, we provide evidence that regulation of CD74-NTF levels by SPPL2a is indispensable for B cell development and function by maintaining trafficking and integrity of MHCII-containing endosomes, highlighting SPPL2a as a promising pharmacological target for depleting and/or modulating B cells.