tbuckley/cabot-search huggingface dataset:
Non-Equilibrium Gating in Cardiac Na <sup>+</sup> Channels
Authors: Colleen E. Clancy, Michihiro Tateyama, Huajun Liu, Xander H.T. Wehrens, Robert S. Kass
Journal: Circulation (2003)

Background— Many long-QT syndrome (LQTS) mutations in the cardiac Na + channel result in a gain of function due to a fraction of channels that fail to inactivate (burst), leading to sustained current (I sus ) during depolarization. However, some Na + channel mutations that are causally linked to cardiac arrhythmia do not result in an obvious gain of function as measured using standard patch-clamp techniques. An example presented here, the SCN5A LQTS mutant I1768V, does not act to increase I sus (&lt;0.1% of peak) compared with wild-type (WT) channels. In fact, it is difficult to reconcile the seemingly innocuous kinetic alterations in I1768V as measured during standard protocols under steady-state conditions with the disease phenotype. Methods and Results— We developed new experimental approaches based on theoretical analyses to investigate Na + channel gating under non-equilibrium conditions, which more closely approximate physiological changes in membrane potential that occur during the course of a cardiac action potential. We used this new approach to investigate channel-gating transitions that occur subsequent to channel activation. Conclusions— Our data suggest an original mechanism for development of LQT-3 arrhythmias. This work demonstrates that a combination of computational and experimental analysis of mutations provides a framework to understand complex mechanisms underlying a range of disorders, from molecular defect to cellular and systems function.
Phase I Trial of BAY 50-4798, an Interleukin-2–Specific Agonist in Advanced Melanoma and Renal Cancer
Authors: Kim Margolin, Michael B. Atkins, Janice P. Dutcher, Marc S. Ernstoff, John W. Smith, Joseph I. Clark, Joseph Baar, Jeffrey Sosman, Jeffrey Weber, Chetan Lathia, Janice Brunetti, Frank Cihon, Brian Schwartz
Journal: Clinical Cancer Research (2007)

Abstract Purpose: BAY 50-4798 is an analogue of interleukin-2 that selectively activates T cells over natural killer cells. This phase I study was designed to determine the maximum tolerated dose (MTD) and safety of BAY 50-4798, screen for tumor response, and assess pharmacokinetics. Experimental Design: Forty-five patients with metastatic melanoma or renal cancer were enrolled, 31 on escalating doses to determine the MTD, with 20 renal cell carcinoma patients treated at MTD to detect antitumor activity. BAY 50-4798 was delivered i.v. every 8 h, days 1 to 5 and 15 to 19, and could be repeated after 9 weeks if tumor was stable or responding. Results: The MTD was defined by and reported in terms of doses received. The doses tested ranged from 1.3 to 26.1 μg/kg, and the MTD was defined as 10.4 μg/kg based on toxicities similar to those of aldesleukin. Two patients achieved partial responses, one with melanoma and one with renal cell carcinoma. Among all 45 patients, 53% and 9% experienced a grade 3 and 4 toxicity, respectively. Among the patients treated at the MTD of 10.4 μg/kg, 71% and 10% experienced a grade 3 and 4 toxicity, respectively. Pharmacokinetics showed dose-dependent peak concentrations (Cmax) and area under the curve with a half-life of ∼2 h and no evidence of accumulation. Lymphocyte subset analysis confirmed the preferential expansion of T-cell subsets over natural killer cells. Conclusions: The antitumor activity of BAY 50-4798 in malignancies that respond to high-dose interleukin-2 was low. BAY 50-4798 might provide advantages over aldesleukin in antigen-specific immunotherapies.
Putting the Rap on Akt
Authors: James E. Thompson, Craig B. Thompson
Journal: Journal of Clinical Oncology (2004)

The protein kinase Akt is activated in a wide variety of cancers, and this activation results in enhanced resistance to apoptosis through multiple mechanisms. This article reviews the control of Akt activation by the opposing actions of the oncogene phosphoinositide 3-kinase (PI3-K) and the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10. The activation of Akt by transforming mutations, such as the amplification of HER-2/neu in breast cancer and the formation of the BCR/ABL fusion gene in chronic myelogenous leukemia, seems to be essential for the transforming activity of these oncogenes. We discuss several of the proposed mechanisms for the antiapoptotic effect of activated Akt, including the inhibition of the proapoptotic protein Bad, downregulation of death receptors, and enhancement of the glycolytic rate. Increased glycolysis is seen in many malignancies and forms the basis for the increasing use of positron emission tomography imaging for diagnosis and staging. Finally, we discuss rapamycin and its analogs, which are now in trials as antineoplastic therapy; these agents show particular promise in tumors in which Akt has been activated.
Antiarrhythmic Efficacy of Selective Blockade of the Cardiac Slowly Activating Delayed Rectifier Current, <i>I</i> <sub> <i>Ks</i> </sub> , in Canine Models of Malignant Ischemic Ventricular Arrhythmia
Authors: Joseph J. Lynch, Melanie S. Houle, Gary L. Stump, Audrey A. Wallace, David B. Gilberto, Hossain Jahansouz, Garry R. Smith, Andrew J. Tebben, Nigel J. Liverton, Harold G. Selnick, David A. Claremon, George E. Billman
Journal: Circulation (1999)

Background —To date, the lack of potent and selective inhibitors has hampered the physiological assessment of modulation of the cardiac slowly activating delayed rectifier current, I Ks . The present study, using the I Ks blocker L-768,673, represents the first in vivo assessment of the cardiac electrophysiological and antiarrhythmic effects of selective I Ks blockade. Methods and Results —In an anesthetized canine model of recent (8.5±0.4 days) anterior myocardial infarction, 0.003 to 0.03 mg/kg L-768,673 IV significantly suppressed electrically induced ventricular tachyarrhythmias and reduced the incidence of lethal arrhythmias precipitated by acute, thrombotically induced posterolateral myocardial ischemia. Antiarrhythmic protection afforded by L-768,673 was accompanied by modest 7% to 10% increases in noninfarct zone ventricular effective refractory period, 3% to 5% increases in infarct zone ventricular effective refractory period, and 4% to 6% increases in QTc interval. In a conscious canine model of healed (3 to 4 weeks) anterior myocardial infarction, ventricular fibrillation was provoked by transient occlusion of the left circumflex coronary artery during submaximal exercise. Pretreatment with 0.03 mg/kg L-768,673 IV elicited a modest 7% increase in QTc, prevented ventricular fibrillation in 5 of 6 animals, and suppressed arrhythmias in 2 additional animals. Conclusions —The present findings suggest that selective blockade of I Ks may be a potentially useful intervention for the prevention of malignant ischemic ventricular arrhythmias.
Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients with tuberculosis.
Authors: S Nicholson, M da G Bonecini-Almeida, J R Lapa e Silva, C Nathan, Q W Xie, R Mumford, J R Weidner, J Calaycay, J Geng, N Boechat, C Linhares, W Rom, J L Ho
Journal: The Journal of Experimental Medicine (1996)

The high-output pathway of nitric oxide production helps protect mice from infection by several pathogens, including Mycobacterium tuberculosis. However, based on studies of cells cultured from blood, it is controversial whether human mononuclear phagocytes can express the corresponding inducible nitric oxide synthase (iNOS;NOS2). The present study examined alveolar macrophages fixed directly after bronchopulmonary lavage. An average of 65% of the macrophages from 11 of 11 patients with untreated, culture-positive pulmonary tuberculosis reacted with an antibody documented herein to be monospecific for human NOS2. In contrast, a mean of 10% of bronchoalveolar lavage cells were positive from each of five clinically normal subjects. Tuberculosis patients' macrophages displayed diaphorase activity in the same proportion that they stained for NOS2, under assay conditions wherein the diaphorase reaction was strictly dependent on NOS2 expression. Bronchoalveolar lavage specimens also contained NOS2 mRNA. Thus, macrophages in the lungs of people with clinically active Mycobacterium tuberculosis infection often express catalytically competent NOS2.
Regulation of Genes of the Circadian Clock in Human Colon Cancer: Reduced Period-1 and Dihydropyrimidine Dehydrogenase Transcription Correlates in High-Grade Tumors
Authors: Walter Krugluger, Anita Brandstaetter, Enikö Kállay, Johann Schueller, Elisabeth Krexner, Stefan Kriwanek, Elisabeth Bonner, Heide S. Cross
Journal: Cancer Research (2007)

Expression of dihydropyrimidine dehydrogenase (DPD) displays a regular daily oscillation in nonmalignant cells. In colorectal cancer cells, the expression of this 5-fluorouracil-metabolizing enzyme is decreased, but the reason remains unclear. In this study, we analyzed by real-time reverse transcription-PCR (RT-PCR) the expression of DPD and of members of the cellular oscillation machinery, period 1 (Per1), period 2 (Per2), and CLOCK, in primary colorectal tumors and normal colon mucosa derived from the same patients. Analysis of tumors according to differentiation grade revealed a 0.46-fold (P = 0.005) decrease for DPD mRNA and a 0.49-fold (P = 0.004) decrease for Per1 mRNA in undifferentiated (G3) tumors compared with paired normal mucosa. In this tumor cohort, the correlation between DPD and Per1 levels was r = 0.64, P < 0.01. In moderately differentiated (G2) colon carcinomas, reduction of DPD and Per1 mRNA levels did not reach significance, but a significant correlation between the respective mRNA levels was detectable (r = 0.54; P < 0.05). The decrease and correlation of DPD and Per1 mRNA levels were even more pronounced in female (G3) patients (DPD: female, 0.35-fold, P < 0.001 versus male, 0.58-fold, P < 0.05; and Per1: female, 0.47-fold, P < 0.01 versus male, 0.52-fold, P < 0.01). The highly significant correlation of DPD mRNA with Per1 mRNA expression suggests control of DPD transcription by the endogenous cellular clock, which is more pronounced in women. Our results also revealed a disturbed transcription of Per1 during tumor progression, which might be the cause for disrupted daily oscillation of DPD in undifferentiated colon carcinoma cells.
Identification and Expression of δ-Isoforms of the Multifunctional Ca <sup>2+</sup> /Calmodulin-Dependent Protein Kinase in Failing and Nonfailing Human Myocardium
Authors: Brigitte Hoch, Rudolf Meyer, Roland Hetzer, Ernst-Georg Krause, Peter Karczewski
Journal: Circulation Research (1999)

Despite its importance for the regulation of heart function, little is known about the isoform expression of the multifunctional Ca2+/calmodulin-dependent protein kinase (CaMKII) in human myocardium. In this study, we investigated the spectrum of CaMKII isoforms delta2, delta3, delta4, delta8, and delta9 in human striated muscle tissue. Isoform delta3 is characteristically expressed in cardiac muscle. In skeletal muscle, specific expression of a new isoform termed delta11 is demonstrated. Complete sequencing of human delta2 cDNA, representing all common features of the investigated CaMKII subclass, revealed its high homology to the corresponding rat cDNA. Comparative semiquantitative reverse transcription-polymerase chain reaction analyses from left ventricular tissues of normal hearts and from patients suffering from dilated cardiomyopathy showed a significant increase in transcript levels of isoform delta3 relative to the expression of glyceraldehyde-3-phosphate dehydrogenase in diseased hearts (101. 6+/-11.0% versus 64.9+/-9.9% in the nonfailing group; P<0.05, n=6). Transcript levels of the other investigated cardiac CaMKII isoforms remained unchanged. At the protein level, by using a subclass-specific antibody, we observed a similar increase of a delta-CaMKII-specific signal (7.2+/-1.0 versus 3.8+/-0.7 optical density units in the nonfailing group; P<0.05, n=4 through 6). The diseased state of the failing hearts was confirmed by a significant increase in transcript levels for atrial natriuretic peptide (292. 9+/-76.4% versus 40.1+/-3.2% in the nonfailing group; P<0.05, n=3 through 6). Our data characterize for the first time the delta-CaMKII isoform expression pattern in human hearts and demonstrate changes in this expression pattern in heart failure.
Metastasis: Quantitative Analysis of Distribution and Fate of Tumor Emboli Labeled With &lt;sup&gt;125&lt;/sup&gt;I-5-Iodo-2′ -deoxyuridine&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: Isaiah J. Fidler
Journal: JNCI Journal of the National Cancer Institute (1970)

125I-5-iodo-2′-deoxyuridine was used to label pure B16 melanoma cells grown in tissue culture. In vitro and in vivo studies established the optimal, nontoxic labeling dose. C57BL/6J mice were given intravenous injections of labeled cells and killed at various intervals after injection. Blood and organs were collected, processed, and monitored. The label was released only after cell death. It was poorly reutilized and quickly eliminated. Hence, organ radioactivity represented almost exclusively the number of live cells present when the animals were killed. The data permitted the following conclusions: The lung contained most of the tumor cells at all intervals. Some tumor cell emboli recirculated. Tumor cells in the lung decreased in numbers at about 5 minutes post injection and returned to high levels by 10 minutes post injection. Tumor cells died rapidly, and about 1% of cells survived after 24 hours. About 400 melanoma cells were in the lung after 14 days, and those yielded an average of 78 metastases. Apparently very few surviving tumor cells are needed to establish a metastasis.
Recommendations for management of patients with neuroendocrine liver metastases
Authors: Andrea Frilling, Irvin M Modlin, Mark Kidd, Christopher Russell, Stefan Breitenstein, Riad Salem, Dik Kwekkeboom, Wan-yee Lau, Catherine Klersy, Valerie Vilgrain, Brian Davidson, Mark Siegler, Martyn Caplin, Enrico Solcia, Richard Schilsky
Journal: The Lancet Oncology (2014)
Pharmacological Rescue of Human K <sup>+</sup> Channel Long-QT2 Mutations
Authors: Sridharan Rajamani, Corey L. Anderson, Blake D. Anson, Craig T. January
Journal: Circulation (2002)

Background — Defective protein trafficking is a consequence of gene mutations. Human long-QT (LQT) syndrome results from mutations in several genes, including the human ether-a-go-go-related gene (HERG), which encodes a delayed rectifier K + current. Trafficking-defective mutant HERG protein is a mechanism for reduced delayed rectifier K + current in LQT2, and high-affinity HERG channel-blocking drugs can result in pharmacological rescue. Methods and Results — We postulated that drug molecules modified to remove high-affinity HERG block may still stabilize mutant proteins in a conformation required for rescue. We tested terfenadine carboxylate (fexofenadine) and terfenadine, structurally similar drugs with markedly different affinities for HERG block, for rescue of trafficking-defective LQT2 mutations. Terfenadine rescued the N470D mutation but blocked the channels. In contrast, fexofenadine rescued N470D with a half-maximal rescue concentration of 177 nmol/L, which is ≈350-fold lower than the half-maximal channel block concentration. The G601S mutation was also rescued without channel block. Conclusions — Pharmacological rescue can occur without channel block. This could represent a new antiarrhythmic paradigm in the treatment of some trafficking-defective LQT2 mutations.
Antitumour activity of an inhibitor of miR-34a in liver cancer with β-catenin-mutations
Authors: Angélique Gougelet, Chiara Sartor, Laura Bachelot, Cécile Godard, Carmen Marchiol, Gilles Renault, Frédéric Tores, Patrick Nitschke, Catherine Cavard, Benoit Terris, Christine Perret, Sabine Colnot
Journal: Gut (2015)

Hepatocellular carcinoma (HCC) is the most prevalent primary tumour of the liver. About a third of these tumours presents activating mutations of the β-catenin gene. The molecular pathogenesis of HCC has been elucidated, but mortality remains high, and new therapeutic approaches, including treatments based on microRNAs, are required. We aimed to identify candidate microRNAs, regulated by β-catenin, potentially involved in liver tumorigenesis.We used a mouse model, in which β-catenin signalling was overactivated exclusively in the liver by the tamoxifen-inducible and Cre-Lox-mediated inactivation of the Apc gene. This model develops tumours with properties similar to human HCC.We found that miR-34a was regulated by β-catenin, and significantly induced by the overactivation of β-catenin signalling in mouse tumours and in patients with HCC. An inhibitor of miR-34a (locked nucleic acid, LNA-34a) exerted antiproliferative activity in primary cultures of hepatocyte. This inhibition of proliferation was associated with a decrease in cyclin D1 levels, orchestrated principally by HNF-4α, a target of miR-34a considered to act as a tumour suppressor in the liver. In vivo, LNA-34a approximately halved progression rates for tumours displaying β-catenin activation together with an activation of caspases 2 and 3.This work demonstrates the key oncogenic role of miR-34a in liver tumours with β-catenin gene mutations. We suggest that patients diagnosed with HCC with β-catenin mutations could be treated with an inhibitor of miR-34a. The potential value of this strategy lies in the modulation of the tumour suppressor HNF-4α, which targets cyclin D1, and the induction of a proapoptotic programme.
Incidental abnormalities found on CT pulmonary angiograms performed for suspected acute pulmonary embolism
Authors: Manish Pagaria, Stephen Crooks, Michael Hughes
Journal: European Respiratory Journal (2011)

A CT pulmonary angiogram (CTPA) is performed commonly in the investigation of suspected pulmonary embolism (PE). Other lung, mediastinal and pleural pathologies of clinical importance may be found incidentally, not suspected from the chest X-ray (CXR). We studied 500 sequential CTPA scans done for suspected PE in a community hospital to assess the nature and frequency of any pulmonary pathology first suggested by the CTPA, with particular reference to pneumonia not diagnosed on the CXR. All CXR and scans were reviewed by a radiologist as well as the treating clinicians.  PE was found in 123 of 500 (24.6%) scans. 110 of 500 (22%) scans showed evidence of pneumonia. Out of these 110 scans, 55 had no evidence of pneumonia on the CXR (of which 63% had been taken within 48 hours of the CTPA). Other pathologies were seen on 145 of 500 scans (29%).   Conclusion:  This study is suggestive of a high incidence of pneumonia in patients scanned for suspected PE, half of whom had no consolidation in the initial CXR. This raises questions concerning the reliability of clinical decisions that rule out pneumonia when there is no consolidation on a CXR.
The V beta 17+ T cell repertoire: skewed J beta usage after thymic selection; dissimilar CDR3s in CD4+ versus CD8+ cells.
Authors: S Candéias, C Waltzinger, C Benoist, D Mathis
Journal: The Journal of Experimental Medicine (1991)

To ascertain how the actual repertoire of T cell receptors (TCRs) deviates from the theoretical, we have generated a large number of junctional region sequences from TCRs carrying the V beta 17 variable region. The greater than 600 sequences analyzed represent transcripts from nine different cell populations, permitting several comparisons: transcripts from an expressed vs. a non-expressed V beta 17 allele, those from E+ vs. E- mice, transcripts from immature vs. mature thymocytes, those from thymic vs. peripheral T cells, and those from CD4+ vs. CD8+ cells. These comparisons have allowed us to distinguish between the influence of molecular events involved in TCR gene rearrangement and that of various selection events that shape the T cell repertoire. Our most striking findings are: (a) that J beta usage is markedly skewed, partly due to recombination mechanics and partly due to selection forces: in particular, those mediated by the class II E molecule in the thymus; and (b) that TCRs on CD4+ and CD8+ cells show intriguing dissimilarities. In addition, we present evidence that N nucleotide additions occur with clear biases, probably due to idiosyncrasies of the recombination enzymes, and provide arguments that TCR and immunoglobulin CDR3s have distinct structures.
In vivo alterations in cardiac metabolism and function in the spontaneously hypertensive rat heart
Authors: M. S. Dodd, D. R. Ball, M. A. Schroeder, L. M. Le Page, H. J. Atherton, L. C. Heather, A.-M. Seymour, H. Ashrafian, H. Watkins, K. Clarke, D. J. Tyler
Journal: Cardiovascular Research (2012)

The aim of this work was to use hyperpolarized carbon-13 ((13)C) magnetic resonance (MR) spectroscopy and cine MR imaging (MRI) to assess in vivo cardiac metabolism and function in the 15-week-old spontaneously hypertensive rat (SHR) heart. At this time point, the SHR displays hypertension and concentric hypertrophy. One of the cellular adaptations to hypertrophy is a reduction in β-oxidation, and it has previously been shown that in response to hypertrophy the SHR heart switches to a glycolytic/glucose-oxidative phenotype.
Should patients positive for HIV infection receive pneumococcal vaccine?
Authors: A Jain, S Jain, V Gant
Journal: BMJ (1995)

Pneumococcal vaccination effectively reduces the incidence of invasive pneumococcal disease in normal subjects. Such invasive pneumococcal disease is 100 times more common in patients with HIV infection than in healthy people, so it seems logical to target this group of patients for vaccination. Few clinics routinely vaccinate patients positive for HIV, despite Department of Health guidelines. This is because of uncertainty about the vaccine's efficacy in HIV disease. There are many reasons to suspect that the vaccine will fail to protect these patients, including the fact that antibodies alone may not be sufficient protection against all serogroups of Pneumococcus and the vaccine works in healthy people but not immunocompromised subjects. Vaccination of HIV positive patients may not be indicated, at least for the time being. The cost of vaccinating such patients in the absence of data showing efficacy may well be less than the cost of a necessarily large and lengthy trial. But the truth must be sought to end current indecision.
Importance of background rates of disease in assessment of vaccine safety during mass immunisation with pandemic H1N1 influenza vaccines
Authors: Steven Black, Juhani Eskola, Claire-Anne Siegrist, Neal Halsey, Noni MacDonald, Barbara Law, Elizabeth Miller, Nick Andrews, Julia Stowe, Daniel Salmon, Kirsten Vannice, Hector S Izurieta, Aysha Akhtar, Mike Gold, Gabriel Oselka, Patrick Zuber, Dina Pfeifer, Claudia Vellozzi
Journal: The Lancet (2009)
Incidence of macrolide resistance in Streptococcus pneumoniae after introduction of the pneumococcal conjugate vaccine: population-based assessment
Authors: David S Stephens, Susu M Zughaier, Cynthia G Whitney, Wendy S Baughman, Lawrence Barker, Kathryn Gay, Delois Jackson, Walter A Orenstein, Kathryn Arnold, Anne Schuchat, Monica M Farley
Journal: The Lancet (2005)