tbuckley/cabot-search huggingface dataset:
Adjuvanting a DNA vaccine with a TLR9 ligand plus Flt3 ligand results in enhanced cellular immunity against the simian immunodeficiency virus
Authors: Marcin Kwissa, Rama R. Amara, Harriet L. Robinson, Bernard Moss, Sefik Alkan, Abdul Jabbar, Francois Villinger, Bali Pulendran
Journal: The Journal of Experimental Medicine (2007)

DNA vaccines offer promising strategies for immunization against infections. However, their clinical use requires improvements in immunogenicity. We explored the efficacy of Toll-like receptor (TLR) ligands (TLR-Ls) on augmenting the immunogenicity of a DNA prime–modified vaccinia virus Ankara (MVA) boost vaccine against SIV. Rhesus macaques were injected with Fms-like tyrosine kinase 3 (Flt3)–ligand (FL) to expand dendritic cells (DCs) and were primed with a DNA vaccine encoding immunodeficiency virus antigens mixed with ligands for TLR9 or TLR7/8. Subsequently, the animals were boosted with DNA and twice with recombinant MVA expressing the same antigens. TLR9-L (CpG DNA) mediated activation of DCs in vivo and enhanced the magnitude of antigen-specific CD8+ interferon (IFN) γ+ T cells and polyfunctional CD8+ T cells producing IFN-γ, tumor necrosis factor α, and interleukin 2. Although this trial was designed primarily as an immunogenicity study, we challenged the animals with pathogenic SIVmac251 and observed a reduction in peak viremia and cumulative viral loads in the TLR9-L plus FL-adjuvanted group relative to the unvaccinated group; however, the study design precluded comparisons between the adjuvanted groups and the group vaccinated with DNA/MVA alone. Viral loads were inversely correlated with the magnitude and quality of the immune response. Thus, the immunogenicity of DNA vaccines can be augmented with TLR9-L plus FL.
Protracted Hypervitaminosis A— Method of Treatment?
Authors: S. J. Iqbal
Journal: JAMA (1983)

<h3>To the Editor.—</h3> We were interested to read of the case of vitamin A poisoning recently described by William A. Farris, MD, and John W. Erdman, MD (1982;247:1317). We note that the symptoms and signs of raised intracranial pressure persisted for over a month after cessation of supplements, and the serum total vitamin A and retinol binding protein levels remained elevated for almost two months. Unfortunately, while the problem of vitamin A poisoning continues to cause concern, no specific form of therapy has been described that might shorten the duration of toxic reaction after heavy overdosage. We have recently described the treatment of a case of vitamin D<sub>2</sub>poisoning by hepatic microsomal enzyme induction using glutethimide.<sup>1</sup>Rapid metabolism of vitamin D to more readily excretable and biologically less active forms has been suggested to occur after hepatic enzyme induction.<sup>2</sup>From what is known of vitamin A metabolism,
The Molecular Basis of Familial Hemolytic Uremic Syndrome
Authors: JESSICA CAPRIOLI, PAOLA BETTINAGLIO, PETER F. ZIPFEL, BARBARA AMADEI, ERICA DAINA, SARA GAMBA, CHRISTINE SKERKA, NICOLA MARZILIANO, GIUSEPPE REMUZZI, MARINA NORIS
Journal: Journal of the American Society of Nephrology (2001)

Abstract. The aim of the present study was to clarify whether factor H mutations were involved in genetic predisposition to hemolytic uremic syndrome, by performing linkage and mutation studies in a large number of patients from those referred to the Italian Registry for Recurrent and Familial HUS/TTP. PCR and Western blot analyses were conducted to characterize the biochemical consequences of the mutations. Five mutations in the factor H gene were identified. Three, identified in two families and in a sporadic case, are heterozygous point mutations within the most C-terminal short consensus repeat 20 (SCR20) of factor H, resulting in single amino acid substitutions. The other two mutations introduce premature stop codons that interrupt the translation of factor H. A heterozygous nonsense mutation was identified in SCR8 in one family, and a homozygous 24-bp deletion within SCR20 was identified in a Bedouin family with a recessive mode of inheritance. Reverse transcription-PCR analysis of cDNA from peripheral blood leukocytes from the Bedouin family showed that the deletion lowered factor H mRNA levels. Although heterozygous mutations were associated with normal factor H levels and incomplete penetrance of the disease, the homozygous mutation in the Bedouin family resulted in severe reduction of factor H levels accompanied by very early disease onset. These data provide compelling molecular evidence that genetically determined deficiencies in factor H are involved in both autosomal-dominant and autosomal-recessive hemolytic uremic syndrome and identify SCR20 as a hot spot for mutations in the disease. The mutations identified here give an important hint to the relevance of the C-terminus of factor H in the control of the alternative complement activation pathway.
PRENATAL DIAGNOSIS OF CONGENITAL ADRENAL HYPERPLASIA (21-HYDROXYLASE DEFICIENCY) BY HLA TYPING
Authors: M.S Pollack, L.S Levine, S Pang, R.P Owens, H.M Nitowsky, B Dupont, D Maurer, M.I New, M Duchon, I.R Merkatz, G Sachs
Journal: The Lancet (1979)
International Union of Pharmacology. XXIII. The Angiotensin II Receptors
Authors: M. de Gasparo, K.J. Catt, T. Inagami, J.W. Wright, Th. Unger
Journal: Pharmacological Reviews (2000)

The cardiovascular and other actions of angiotensin II (Ang II) are mediated by AT(1) and AT(2) receptors, which are seven transmembrane glycoproteins with 30% sequence similarity. Most species express a single autosomal AT(1) gene, but two related AT(1A) and AT(1B) receptor genes are expressed in rodents. AT(1) receptors are predominantly coupled to G(q/11), and signal through phospholipases A, C, D, inositol phosphates, calcium channels, and a variety of serine/threonine and tyrosine kinases. Many AT(1)-induced growth responses are mediated by transactivation of growth factor receptors. The receptor binding sites for agonist and nonpeptide antagonist ligands have been defined. The latter compounds are as effective as angiotensin converting enzyme inhibitors in cardiovascular diseases but are better tolerated. The AT(2) receptor is expressed at high density during fetal development. It is much less abundant in adult tissues and is up-regulated in pathological conditions. Its signaling pathways include serine and tyrosine phosphatases, phospholipase A(2), nitric oxide, and cyclic guanosine monophosphate. The AT(2) receptor counteracts several of the growth responses initiated by the AT(1) and growth factor receptors. The AT(4) receptor specifically binds Ang IV (Ang 3-8), and is located in brain and kidney. Its signaling mechanisms are unknown, but it influences local blood flow and is associated with cognitive processes and sensory and motor functions. Although AT(1) receptors mediate most of the known actions of Ang II, the AT(2) receptor contributes to the regulation of blood pressure and renal function. The development of specific nonpeptide receptor antagonists has led to major advances in the physiology, pharmacology, and therapy of the renin-angiotensin system.
Controlled Trial of Psychotherapy for Congolese Survivors of Sexual Violence
Authors: Judith K. Bass, Jeannie Annan, Sarah McIvor Murray, Debra Kaysen, Shelly Griffiths, Talita Cetinoglu, Karin Wachter, Laura K. Murray, Paul A. Bolton
Journal: New England Journal of Medicine (2013)

Survivors of sexual violence have high rates of depression, anxiety, and post-traumatic stress disorder (PTSD). Although treatment for symptoms related to sexual violence has been shown to be effective in high-income countries, evidence is lacking in low-income, conflict-affected countries.In this trial in the Democratic Republic of Congo, we randomly assigned 16 villages to provide cognitive processing therapy (1 individual session and 11 group sessions) or individual support to female sexual-violence survivors with high levels of PTSD symptoms and combined depression and anxiety symptoms. One village was excluded owing to concern about the competency of the psychosocial assistant, resulting in 7 villages that provided therapy (157 women) and 8 villages that provided individual support (248 women). Assessments of combined depression and anxiety symptoms (average score on the Hopkins Symptom Checklist [range, 0 to 3, with higher scores indicating worse symptoms]), PTSD symptoms (average score on the PTSD Checklist [range, 0 to 3, with higher scores indicating worse symptoms]), and functional impairment (average score across 20 tasks [range, 0 to 4, with higher scores indicating greater impairment]) were performed at baseline, at the end of treatment, and 6 months after treatment ended.A total of 65% of participants in the therapy group and 52% of participants in the individual-support group completed all three assessments. Mean scores for combined depression and anxiety improved in the individual-support group (2.2 at baseline, 1.7 at the end of treatment, and 1.5 at 6 months after treatment), but improvements were significantly greater in the therapy group (2.0 at baseline, 0.8 at the end of treatment, and 0.7 at 6 months after treatment) (P<0.001 for all comparisons). Similar patterns were observed for PTSD and functional impairment. At 6 months after treatment, 9% of participants in the therapy group and 42% of participants in the individual-support group met criteria for probable depression or anxiety (P<0.001), with similar results for PTSD.In this study of sexual-violence survivors in a low-income, conflict-affected country, group psychotherapy reduced PTSD symptoms and combined depression and anxiety symptoms and improved functioning. (Funded by the U.S. Agency for International Development Victims of Torture Fund and the World Bank; ClinicalTrials.gov number, NCT01385163.).
Remote Magnetic Navigation to Guide Endocardial and Epicardial Catheter Mapping of Scar-Related Ventricular Tachycardia
Authors: Arash Aryana, Andre d’Avila, E. Kevin Heist, Theofanie Mela, Jagmeet P. Singh, Jeremy N. Ruskin, Vivek Y. Reddy
Journal: Circulation (2007)

The present study examines the safety and feasibility of using a remote magnetic navigation system to perform endocardial and epicardial substrate-based mapping and radiofrequency ablation in patients with scar-related ventricular tachycardia (VT).Using the magnetic navigation system, we performed 27 procedures on 24 consecutive patients with a history of VT related to myocardial infarction, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, or sarcoidosis. Electroanatomic mapping of the left ventricular, right ventricular, and ventricular epicardial surfaces was constructed in 24, 10, and 12 patients, respectively. Complete-chamber VT activation maps were created in 4 patients. A total of 77 VTs were inducible, of which 21 were targeted during VT with the remotely navigated radiofrequency ablation catheter alone. With a combination of entrainment and activation mapping, 17 of 21 VTs (81%) were successfully terminated in a mean of 8.4+/-8.2 seconds; for the remainder, irrigated radiofrequency ablation was necessary. The mean fluoroscopy times for endocardial and epicardial mapping were 27+/-23 seconds (range, 0 to 105 seconds) and 18+/-18 seconds (range, 0 to 49 seconds), respectively. In concert with a manually navigated irrigated ablation catheter, 75 of 77 VTs (97%) were ultimately ablated. Four patients underwent a second procedure for recurrent VT, 3 with the magnetic navigation system. After 1.2 procedures per patient, VT did not recur during a mean follow-up of 7+/-3 months (range, 2 to 12 months).The present study demonstrates the safety and feasibility of remote catheter navigation to perform substrate mapping of scar-related VT in a wide range of disease states with a minimal amount of fluoroscopy exposure.
Stable low-level expression of p21WAF1/CIP1 in A549 human bronchogenic carcinoma cell line-derived clones down-regulates E2F1 mRNA and restores cell proliferation control
Authors: Timothy G Graves, Michael W Harr, Erin L Crawford, James C Willey
Journal: Molecular Cancer (2006)

Abstract Background Deregulated cell cycle progression and loss of proliferation control are key properties of malignant cells. In previous studies, an interactive transcript abundance index (ITAI) comprising three cell cycle control genes, [MYC × E2F1]/p21 accurately distinguished normal from malignant bronchial epithelial cells (BEC), using a cut-off threshold of 7,000. This cut-off is represented by a line with a slope of 7,000 on a bivariate plot of p21 versus [MYC × E2F1], with malignant BEC above the line and normal BEC below the line. This study was an effort to better quantify, at the transcript abundance level, the difference between normal and malignant BEC. The hypothesis was tested that experimental elevation of p21 in a malignant BEC line would decrease the value of the [MYC × E2F1]/p21 ITAI to a level below this line, resulting in loss of immortality and limited cell population doubling capacity. In order to test the hypothesis, a p21 expression vector was transfected into the A549 human bronchogenic carcinoma cell line, which has low constitutive p21 TA expression relative to normal BEC. Results Following transfection of p21, four A549/p21 clones with stable two-fold up-regulated p21 expression were isolated and expanded. For each clone, the increase in p21 transcript abundance (TA) was associated with increased total p21 protein level, more than 5-fold reduction in E2F1 TA, and 10-fold reduction in the [MYC × E2F1]/p21 ITAI to a value below the cut-off threshold. These changes in regulation of cell cycle control genes were associated with restoration of cell proliferation control. Specifically, each transfectant was capable of only 15 population doublings compared with unlimited population doublings for parental A549. This change was associated with an approximate 2-fold increase in population doubling time to 38.4 hours (from 22.3 hrs), resumption of contact-inhibition, and reduced dividing cell fraction as measured by flow cytometric DNA analysis. Conclusion These results, likely due to increased p21-mediated down-regulation of E2F1 TA at the G1/S phase transition, are consistent with our hypothesis. Specifically, they provide experimental confirmation that a line with slope of 7,000 on the p21 versus [MYC × E2F1] bivariate plot quantifies the difference between normal and malignant BEC at the level of transcript abundance.
Differential Regulation of Hyaluronic Acid Synthase Isoforms in Human Saphenous Vein Smooth Muscle Cells
Authors: M. van den Boom, M. Sarbia, K. von Wnuck Lipinski, P. Mann, J. Meyer-Kirchrath, B.H. Rauch, K. Grabitz, B. Levkau, K. Schrör, J.W. Fischer
Journal: Circulation Research (2005)

Autologous saphenous vein bypass grafts (SVG) are frequently compromised by neointimal thickening and subsequent atherosclerosis eventually leading to graft failure. Hyaluronic acid (HA) generated by smooth muscle cells (SMC) is thought to augment the progression of atherosclerosis. The aim of the present study was (1) to investigate HA accumulation in native and explanted arterialized SVG, (2) to identify factors that regulate HA synthase (HAS) expression and HA synthesis, and (3) to study the function of the HAS2 isoform. In native SVG, expression of all 3 HAS isoforms was detected by RT-PCR. Histochemistry revealed that native and arterialized human saphenous vein segments were characterized by marked deposition of HA in association with SMC. Interestingly, in contrast to native SVG, cyclooxygenase (COX)-2 expression by SMC and macrophages was detected only in arterialized SVG. In vitro in human venous SMC HAS isoforms were found to be differentially regulated. HAS2, HAS1, and HA synthesis were strongly induced by vasodilatory prostaglandins via G s -coupled prostaglandin receptors. In addition, thrombin induced HAS2 via activation of PAR1 and interleukin 1β was the only factor that induced HAS3. By small interfering RNA against HAS2, it was shown that HAS2 mediated HA synthesis is critically involved in cell cycle progression through G 1 /S phase and SMC proliferation. In conclusion, the present study shows that HA-rich extracellular matrix is maintained after arterialization of vein grafts and might contribute to graft failure because of its proproliferative function in venous SMC. Furthermore, COX-2–dependent prostaglandins may play a key role in the regulation of HA synthesis in arterialized vein grafts.
Molecular Pathways: Is AMPK a Friend or a Foe in Cancer?
Authors: D. Grahame Hardie
Journal: Clinical Cancer Research (2015)

Abstract The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status expressed in essentially all eukaryotic cells. Once activated by energetic stress via a mechanism that detects increases in AMP:ATP and ADP:ATP ratios, AMPK acts to restore energy homeostasis by switching on catabolic pathways that generate ATP, while switching off ATP-consuming processes, including anabolic pathways required for cell growth and proliferation. AMPK activation promotes the glucose-sparing, oxidative metabolism utilized by most quiescent cells, rather than the rapid glucose uptake and glycolysis used by most proliferating cells. Numerous pharmacologic activators of AMPK are known, including drugs in long use such as salicylate and metformin, and there is evidence that regular use of either of the latter provides protection against development of cancer. Tumor cells appear to be under selection pressure to downregulate AMPK, thus limiting its restraining influence on cell growth and proliferation, and several interesting mechanisms by which this occurs are discussed. Paradoxically, however, a complete loss of AMPK function, which appears to be rare in human cancers, may be deleterious to survival of tumor cells. AMPK can therefore be either a friend or a foe in cancer, depending on the context. Clin Cancer Res; 21(17); 3836–40. ©2015 AACR.
Genetic susceptibility to asbestos-related fibrotic pleuropulmonary changes
Authors: M. K. Kukkonen, S. Hamalainen, S. Kaleva, T. Vehmas, M. S. Huuskonen, P. Oksa, H. Vainio, P. Piirila, A. Hirvonen
Journal: European Respiratory Journal (2010)

The objective of this study was to determine whether genetic polymorphisms in enzymes that metabolise oxidative agents modify the individual susceptibility to developing asbestos and smoking-related pleuropulmonary changes. Nine polymorphisms of six genes (<i>EPHX1</i>, <i>GSTM1</i>, <i>GSTM3</i>, <i>GSTP1, GSTT1</i> and<i> NAT2</i>) were genotyped from 1,008 Finnish asbestos-exposed workers. The genotype data were compared to signs of lung fibrosis and pleural thickenings, as well as with total lung capacity, single-breath diffusing capacity of the lung for carbon monoxide (<i>D</i><sub>L,CO</sub>) and specific diffusing capacity (expressed as <i>D</i><sub>L,CO</sub> per unit of alveolar volume (<i>V</i><sub>A</sub>)). The <i>GSTT1</i> deletion polymorphism was associated with fibrotic changes (p=0.003), and decreased <i>D</i><sub>L,CO</sub> (p=0.02) and <i>D</i><sub>L,CO</sub>/<i>V</i><sub>A</sub> (p=0.002), and the <i>GSTM1</i> deletion polymorphism was associated with the greatest thickness of pleural plaques (p=0.009). On further analysis, the <i>GSTT1</i> null genotype was found to pose over a three-fold risk for severe fibrotic changes (OR 3.12, 95% CI 1.51–6.43), and around two-fold risks for decreased <i>D</i><sub>L,CO</sub> (OR 1.77, 95% CI 1.06–2.95) and <i>D</i><sub>L,CO</sub>/<i>V</i><sub>A</sub> (OR 2.37, 95% CI 1.33–4.23). In addition, the <i>GSTM1</i> null genotype showed an elevated risk (OR 1.36, 95% CI 1.03–1.80) for thicker pleural plaques. Our data suggest that inherited detoxification capacity may affect the development and severity of asbestos and smoking-related nonmalignant pulmonary changes.
Clinical significance of urokinase‐type plasminogen activator receptor (uPAR) expression in cancer
Authors: Charles Edo de Bock, Yao Wang
Journal: Medicinal Research Reviews (2003)

Abstract The involvement of the urokinase‐type plasminogen activator (uPA) system in particular has been extensively studied in the pathogenesis of cancer. The molecular role of the uPA receptor (uPAR) is well characterized with its participation in cell migration and extracellular matrix (ECM) degradation. Over‐expression of uPAR in cancer has been demonstrated in many studies and is considered an attractive target for anticancer agents. We and others have down‐regulated uPAR expression in an attempt to inhibit cancer metastasis based on its molecular role. Uniquely, uPAR which is a glycosyl phosphatidylinositol anchored protein is not only bound to the cell surface but also has a soluble form, suPAR. There is now accumulated clinical and experimental evidence supporting the significant role of uPAR and its soluble counterpart in a number of solid cancers. The expression of uPAR can be associated with tumor cells or stromal cells or both. Differences observed in the expression of uPAR using immunohistochemistry (IHC) are likely explained by the use of different antibodies and techniques rather than true cellular differences and are reviewed here. This review summarizes the clinical relevance of uPAR and its soluble form in the prognosis and diagnosis of different cancers. © 2003 Wiley Periodicals, Inc. Med Res Rev, 24, No. 1, 13–39, 2004
Nuclear PARP-1 protein overexpression is associated with poor overall survival in early breast cancer
Authors: F Rojo, J García-Parra, S Zazo, I Tusquets, J Ferrer-Lozano, S Menendez, P Eroles, C Chamizo, S Servitja, N Ramírez-Merino, F Lobo, B Bellosillo, J M Corominas, J Yelamos, S Serrano, A Lluch, A Rovira, J Albanell
Journal: Annals of Oncology (2011)
Molecular Basis for CA2+ Channel Diversity
Authors: F Hofmann, M Biel, V Flockerzi
Journal: Annual Review of Neuroscience (1994)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial
Authors: María-Victoria Mateos, Albert Oriol, Joaquín Martínez-López, Norma Gutiérrez, Ana-Isabel Teruel, Raquel de Paz, José García-Laraña, Enrique Bengoechea, Alejandro Martín, Joaquín Díaz Mediavilla, Luis Palomera, Felipe de Arriba, Yolanda González, Jose-Mariano Hernández, Ana Sureda, José-Luis Bello, Joan Bargay, Francisco-Javier Peñalver, José-María Ribera, María-Luisa Martín-Mateos, Ramón García-Sanz, María-Teresa Cibeira, María-Luisa Martín Ramos, María-Belén Vidriales, Bruno Paiva, María-Angeles Montalbán, Juan-José Lahuerta, Joan Bladé, Jesús-Fernando San Miguel
Journal: The Lancet Oncology (2010)