tbuckley/cabot-search huggingface dataset:
Transient expression of interleukin 2 receptors. Consequences for T cell growth.
Authors: D A Cantrell, K A Smith
Journal: The Journal of Experimental Medicine (1983)

T lymphocyte mitosis results from the interaction of interleukin 2 (IL-2) with specific receptors that appear only after appropriate immune stimulation. To assess the potential role of IL-2 receptor levels in determining the rate and magnitude of T cell proliferation, the expression of IL-2 receptors by lectin-stimulated human peripheral blood T cells was examined and correlated with T cell growth. Using biosynthetically radiolabeled IL-2 and anti-Tac, a monoclonal antibody that blocks IL-2 receptor binding, IL-2 receptors were found to accumulate slowly and asynchronously among lectin-stimulated T cells and to precede the onset of DNA synthesis. Moreover, a critical threshold of IL-2 receptor density appeared to be required before the commitment to cell cycle progression, as analyzed quantitatively by tritiated thymidine incorporation and flow cytometric analysis of cellular DNA content. Once maximal IL-2 receptor expression occurred, continued proliferation was IL-2 concentration dependent as assessed using homogenous immunoaffinity-purified IL-2. Upon removal of the activating lectin, IL-2 receptor levels progressively declined, and, in parallel, the rate of proliferation diminished. The decay of IL-2 receptors could not be attributed to IL-2-mediated down-regulation. Instead, renewed IL-2 receptor expression was dependent upon the reintroduction of the initial activating signal. Repetitive exposure to lectin resulted in a more rapid reexpression of maximal IL-2 receptor levels, which was then followed by an accelerated resumption of proliferation. Thus, the extent of T cell proliferation after immune stimulation depends upon the interplay of the IL-2 concentration available and the density of IL-2 receptors expressed, both of which are ultimately determined by antigen/lectin stimulation. The awareness of the transience and the antigen/lectin dependence of IL-2 receptor expression, together with the capacity to monitor T cell cultures for IL-2 receptor levels, should facilitate the initiation and maintenance of cloned, antigen-specific T cells in long-term culture. In addition, these findings suggest that, in vivo, the rapidity of acquisition of maximum IL-2 receptor levels by activated T cells and the duration of IL-2 receptor expression may well direct the magnitude of T cell clonal expansion and resultant immune responses.
Cationic liposomal paclitaxel plus gemcitabine or gemcitabine alone in patients with advanced pancreatic cancer: a randomized controlled phase II trial
Authors: J.M. Löhr, S.L. Haas, W.-O. Bechstein, G. Bodoky, K. Cwiertka, W. Fischbach, U.R. Fölsch, D. Jäger, D. Osinsky, J. Prausova, W.E. Schmidt, M.P. Lutz
Journal: Annals of Oncology (2011)
Matrix Metalloproteinase-7 Facilitates Insulin-Like Growth Factor Bioavailability through Its Proteinase Activity on Insulin-Like Growth Factor Binding Protein 3
Authors: Shin’ichi Miyamoto, Keiichi Yano, Seiji Sugimoto, Genichiro Ishii, Takahiro Hasebe, Yasushi Endoh, Keiji Kodama, Masato Goya, Tsutomu Chiba, Atsushi Ochiai
Journal: Cancer Research (2004)

Abstract Matrix metalloproteinase-7 (MMP-7) secreted by cancer cells has been implicated classically in the basement membrane destruction associated with tumor cell invasion and metastasis. Recent epidemiologic studies have established a correlation between high levels of circulating insulin-like growth factor (IGF) and low levels of IGF binding protein 3 (IGFBP-3), and relative risk of developing colon, breast, prostate, and lung cancer, which are known to produce MMP-7. In this study, IGFBP-3 was assessed as a candidate for the physiologic substrate of MMP-7. MMP-7 proteolysis generated four major fragments (26 kDa, 17 kDa, 15.5 kDa, and 15.5 kDa), and two cleavage sites were identified: one at the site of hydrolysis of the K144-I145 peptide bond and one at the R95-L96 peptide bond. The former site is different from the previously reported site of cleavage of IGFBP-3 by other proteases. Addition of IGFBP-3 inhibited IGF-I-mediated IGF type 1 receptor (IGF-IR) phosphorylation and activation of the downstream molecule Akt in BALB/c 3T3 fibroblasts overexpressing human IGF-IR (3T3-IGF-IR) and in two human colon cancer cell lines (COLO201 and HT29). Coincubation of the IGF-I/IGFBP-3 complex with MMP-7 restored IGF-I-mediated IGF-IR phosphorylation and activation of Akt in these cell lines. The IGF-I signal recovered by MMP-7 protected against apoptosis induced by anoikis in 3T3-IGF-IR cells. These results indicate that MMP-7 proteolysis of IGFBP-3 plays a crucial role in regulating IGF-I bioavailability, thereby promoting cell survival. This mechanism may contribute to the tumorigenesis of MMP-7-producing IGF-IR-expressing tumors in the primary site and to organ-specific metastasis in a paracrine manner.
Atrial natriuretic factor potentiates forearm reflex vasoconstriction induced by cardiopulmonary receptor deactivation in man.
Authors: M Volpe, N De Luca, M C Bigazzi, F Vecchione, G Lembo, M Condorelli, B Trimarco
Journal: Circulation (1988)

Previous evidence suggests that atrial natriuretic factor (ANF) interferes with the autonomic control of circulation. In the present study we investigated whether ANF modulates forearm vasoconstriction reflexly induced by cardiopulmonary receptor unloading in man. For this purpose, the hemodynamic response to -20 mm Hg lower body negative pressure (LBNP) was assessed under control conditions and during the constant infusion of alpha-human ANF (0.5 micrograms/kg bolus followed by 0.05 micrograms/kg/min) in seven normal subjects. ANF infusion resulted in a slight reduction in blood pressure and right atrial pressure, did not modify heart rate or forearm vascular resistance, but significantly potentiated the reflex increase in forearm vascular resistance during LBNP (+25 +/- 9% under control conditions vs +40 +/- 12% during ANF, p less than .05). In an attempt to clarify the mechanisms underlying the enhanced reflex vasoconstriction during infusion of ANF, in five additional subjects we demonstrated that there was a comparable vascular reflex response to LBNP under control conditions and during nitroglycerin infusion at a dose that induced a reduction in atrial pressure comparable to that observed during ANF. Finally, in seven additional subjects we found that ANF infusion did not alter the reflex hemodynamic responses elicited by carotid baroreceptor unloading induced by a +60 mm Hg increase in external neck pressure. We conclude that during the infusion of a pharmacologic dose of ANF the reflex forearm vasoconstriction in response to selective cardiopulmonary receptor unloading is potentiated. This effect does not seem to be related to the hemodynamic actions of the peptide or to interference with the sympathetic control of peripheral circulation.
AceView: a comprehensive cDNA-supported gene and transcripts annotation
Authors: Danielle Thierry-Mieg, Jean Thierry-Mieg
Journal: Genome biology (2006)

Regions covering one percent of the genome, selected by ENCODE for extensive analysis, were annotated by the HAVANA/Gencode group with high quality transcripts, thus defining a benchmark. The ENCODE Genome Annotation Assessment Project (EGASP) competition aimed at reproducing Gencode and finding new genes. The organizers evaluated the protein predictions in depth. We present a complementary analysis of the mRNAs, including alternative transcript variants.We evaluate 25 gene tracks from the University of California Santa Cruz (UCSC) genome browser. We either distinguish or collapse the alternative splice variants, and compare the genomic coordinates of exons, introns and nucleotides. Whole mRNA models, seen as chains of introns, are sorted to find the best matching pairs, and compared so that each mRNA is used only once. At the mRNA level, AceView is by far the closest to Gencode: the vast majority of transcripts of the two methods, including alternative variants, are identical. At the protein level, however, due to a lack of experimental data, our predictions differ: Gencode annotates proteins in only 41% of the mRNAs whereas AceView does so in virtually all. We describe the driving principles of AceView, and how, by performing hand-supervised automatic annotation, we solve the combinatorial splicing problem and summarize all of GenBank, dbEST and RefSeq into a genome-wide non-redundant but comprehensive cDNA-supported transcriptome. AceView accuracy is now validated by Gencode.Relative to a consensus mRNA catalog constructed from all evidence-based annotations, Gencode and AceView have 81% and 84% sensitivity, and 74% and 73% specificity, respectively. This close agreement validates a richer view of the human transcriptome, with three to five times more transcripts than in UCSC Known Genes (sensitivity 28%), RefSeq (sensitivity 21%) or Ensembl (sensitivity 19%).
Pretreatment with Dexamethasone Increases Antitumor Activity of Carboplatin and Gemcitabine in Mice Bearing Human Cancer Xenografts
Authors: Hui Wang, Mao Li, John J. Rinehart, Ruiwen Zhang
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The present study was undertaken to determine the effects of dexamethasone (DEX) pretreatment on antitumor activity and pharmacokinetics of the cancer chemotherapeutic agents carboplatin and gemcitabine. Experimental Design: Antitumor activities of carboplatin and gemcitabine with or without DEX pretreatment were determined in six murine-human cancer xenograft models, including cancers of colon (LS174T), lung (A549 and H1299), and breast (MCF-7 and MDA-MB-468) and glioma (U87-MG). Effects of DEX on plasma and tissue pharmacokinetics of carboplatin and gemcitabine were also determined by using the LS174T, A549, and H1299 models. Results: Although DEX alone showed minimal antitumor activity, DEX pretreatment significantly increased the efficacy of carboplatin, gemcitabine, or a combination of both drugs by 2–4-fold in all xenograft models tested. Without DEX treatment, the tumor exposure to carboplatin, measured by the area under the curve, was markedly lower than normal tissues. However, DEX pretreatment significantly increased tumor carboplatin levels, including 200% increase in area under the curve, 100% increase in maximum concentration, and 160% decrease in clearance. DEX pretreatment similarly increased gemcitabine uptake in tumors. Conclusions: To our knowledge, this is the first report that DEX significantly enhances the antitumor activity of carboplatin and gemcitabine and increases their accumulation in tumors. These results provide a basis for further evaluation of DEX as a chemosensitizer in patients.
Engineering the Response to Vascular Injury
Authors: David A. Goukassian, Raj Kishore, Kevin Krasinski, Christine Dolan, Corinne Luedemann, Young-sup Yoon, Marianne Kearney, Allison Hanley, Hong Ma, Takayuki Asahara, Jeffrey M. Isner, Douglas W. Losordo
Journal: Circulation Research (2003)

Tumor necrosis factor-alpha (TNF-alpha) is expressed locally in the vessel wall after angioplasty and induces growth arrest and apoptosis in endothelial cells (ECs), thereby delaying reendothelialization. Prior studies have shown that direct antagonism of TNF-alpha, using a systemically administered soluble receptor, can enhance endothelial recovery and reduce neointimal thickening. These studies have also shown that downregulation of the transcription factor E2F1 was a key mechanism of TNF's effect on ECs. We now show that Ad-E2F1 overexpression at sites of balloon injury accelerates functional endothelial recovery, consistent with the prior in vitro findings. Moreover these studies also reveal divergent effects of TNF-alpha and overexpression of E2F1 on ECs versus VSMCs. TNF-alpha exposure of VSMCs had no affect on proliferation or apoptosis, in contrast to the effect seen in ECs. In Ad-E2F1-transduced VSMCs, however, TNF-alpha-induced marked apoptosis in contrast to the survival effect seen in ECs. Finally, these studies suggest that differential activation of NF-kappaB may play a key role in mediating these opposing effects. Nuclear translocation and transcriptional activity of NF-kappaB was markedly attenuated in Ad-E2F1-transduced VSMCs, whereas it remained active in similarly treated ECs when the cells were exposed to TNF-alpha. These studies reveal that overexpression of Ad-E2F1 primes VSMCs to TNF-alpha-induced apoptosis. Furthermore, E2F1 potentiates VSMC death by blocking antiapoptotic signaling pathway through inhibition of NF-kappaB activation. The divergent responses of VSMCs and ECs to E2F1 overexpression provide unique therapeutic possibilities: simultaneously targeting the cell cycle of two different cell types, within same tissue microenvironment resulting in opposite and biologically complimentary effects.
Fibroids: diagnosis and management
Authors: Mary Ann Lumsden, Ibraheem Hamoodi, Janesh Gupta, Martha Hickey
Journal: BMJ (2015)

#### The bottom line Uterine leiomyomas (fibroids) are the most common benign tumours in women. They may be single or multiple and their size varies from a few millimetres to 30 cm or more. By age 50 nearly 70% of white women and more than 80% of black women have had at least one fibroid.1 Box 1 lists the several risk factors for fibroids. Symptomatic fibroids are often managed surgically, and this confers a considerable burden on healthcare costs.2 This review aims to update non-specialists on the investigation and management of fibroids. Gaps in current knowledge are highlighted. #### Sources and selection criteria The literature search used a combination of MeSH, text words, and appropriate word variants of "fibroids" and "leiomyoma". We searched Medline and Embase, Cochrane Reviews, personal references and reference lists in general articles on uterine fibroids. Searching was limited to publications in English and to studies in women and we have included reference to evidence based guidelines, such as those by the National Institute of Health and Care Excellence. #### Box 1 Risk factors for uterine fibroids
Active screening at entry for tuberculosis among new immigrants: a systematic review and meta-analysis
Authors: S. Arshad, L. Bavan, K. Gajari, S. N. J. Paget, I. Baussano
Journal: European Respiratory Journal (2009)

Although there is no evidence that imported tuberculosis increases the incidence of the disease in host countries, the rise in migration worldwide raises concerns regarding the adequacy of surveillance and control of immigrant-associated tuberculosis in low incidence countries. Assessing the performance of screening of immigrants for tuberculosis is key to rationalising control policies for the detection and management of immigrant-associated tuberculosis. We performed a systematic review and meta-analysis to determine the yield of active screening for tuberculosis among new immigrants at the point of entry. The yield for pulmonary tuberculosis was 3.5 cases per 1,000 screened (95% CI 2.9–4.1; I<sup>2</sup> = 94%); for refugees, asylum seekers and regular immigrants the estimates were 11.9 (95% CI 6.7–17.2; I<sup>2</sup> = 92%), 2.8 (95% CI 2.0–3.7; I<sup>2</sup> = 96%) and 2.7 (95% CI 2.0–3.4; I<sup>2</sup> = 81%), respectively. The yield estimates for immigrants from Europe, Africa and Asia were 2.4 (95% CI 1.3–3.4; I<sup>2</sup> = 51.5%), 6.5 (95% CI 3.2–10.0; I<sup>2</sup> = 62%) and 11.2 (95% CI 6.2–16.1; I<sup>2</sup> = 95%), respectively. These results provide useful data to inform the development of coherent policies and rational screening services for the detection of immigrant-associated tuberculosis.
Causes of failure of eradication of Helicobacter pylori
Authors: P. J Jenks
Journal: BMJ (2002)

Eradication of Helicobacter pylori from the gastric and duodenal mucosa of infected patients is the most important goal in the management of peptic ulcer disease and other conditions associated with H pylori .1 The survival capabilities of H pylori in the stomach make it difficult to eradicate, and effective treatment requires multidrug regimens consisting of two antibiotics (usually selected from clarithromycin, metronidazole, amoxicillin, and tetracycline), combined with acid suppressants and bismuth compounds.2 A significant proportion of patients do not respond to treatment, and adverse treatment outcome is associated with advanced age, smoking, high intragastric bacterial load before treatment, bacterial genotype, and host genetic polymorphisms of the cytochrome-P450 isoenzymes that are specifically involved in the metabolism of proton pump inhibitors.3 Adherence to the drug regimen is particularly important for successful eradication of infection and can be improved by education of patients and programmes to improve compliance.4 But as in many other infectious diseases, antibiotic resistance is the major cause of treatment failure. Meta-analyses have established beyond doubt that resistance to either the macrolide or 5-nitroimidazole component …
Protective Role of Ecto-5′-Nucleotidase (CD73) in Renal Ischemia
Authors: Almut Grenz, Hua Zhang, Tobias Eckle, Michel Mittelbronn, Manfred Wehrmann, Christoph Köhle, Doris Kloor, Linda F. Thompson, Hartmut Osswald, Holger K. Eltzschig
Journal: Journal of the American Society of Nephrology (2007)

Acute renal failure from ischemia significantly contributes to cardiovascular morbidity and mortality. Extracellular adenosine has been implicated as an anti-inflammatory metabolite particularly during conditions of limited oxygen availability (e.g., ischemia). Because ecto-5'-nucleotidase (CD73) is rate limiting for extracellular adenosine generation, this study examined the contribution of CD73-dependent adenosine production to ischemic preconditioning (IP) of the kidneys. After the initial observation that murine CD73 transcript, protein, and function are induced by renal IP, its role in IP-mediated kidney protection was studied. In fact, increases in renal adenosine concentration with IP are attenuated in cd73(-/-) mice. Moreover, pharmacologic inhibition of CD73 or its targeted gene deletion abolished renal protection by IP as measured by clearance studies, plasma electrolytes, and renal tubular destruction, and reconstitution of cd73(-/-) mice with soluble 5'-nucleotidase resulted in complete restoration of renal protection by IP. Finally, renal injury after ischemia was attenuated by intraperitoneal treatment of wild-type mice with soluble 5'-nucleotidase to a similar degree as by IP. Taken together, these data reveal what is believed to be a previously unrecognized role of CD73 in renal protection from ischemia and suggest treatment with soluble 5'-nucleotidase as a novel therapeutic approach in the treatment of renal diseases that are precipitated by limited oxygen availability.
A New Technique for the Study of Left Ventricular Pressure-Volume Relations in Man
Authors: LAMBERT P. McLAURIN, WILLIAM GROSSMAN, MILTIADIS A. STEFADOUROS, ELLIS L. ROLETT, DANIEL T. YOUNG
Journal: Circulation (1973)

Study of left ventricular pressure-volume relations in man has been limited by technical problems associated with left ventricular angiography. A new approach to this problem using simultaneous recording of left ventricular pressure and left ventricular volume (determined by echocardiography) was applied in 21 patients. Pressure-volume plots, constructed from pressure and volume values sampled at 20 or 40 msec intervals, had characteristic shapes for the states studied: normal, pressure overload, volume overload, and myocardial disease. These curves closely resembled pressure-volume plots previously determined by others from quantitative angiography. The area inscribed by these plots was integrated to calculate left ventricular stroke work. Left ventricular stroke work index (gram-meters/m 2 ) was in the range previously reported for the various states; normal-41 ± 12, pressure overload-102 ± 14, volume overload-136 ± 36, myocardial disease-65 ± 19. Inspection of the pressure-volume plots allowed assessment of valvular regurgitation by the characteristic deformation of the loop during "isovolumic" contraction and relaxation. Study of diastolic filling allowed qualitative assessment of left ventricular compliance. Patients with pressure overload had stiffer ventricles, with high diastolic pressure at lower volume, than normal or volume overload patients. In summary, a new method is described for the beat-to-beat analysis of left ventricular pressure-volume relations in man.
Immunohistochemistry to identify EGFR mutations or ALK rearrangements in patients with lung adenocarcinoma
Authors: P. Hofman, M. Ilie, V. Hofman, S. Roux, A. Valent, A. Bernheim, M. Alifano, F. Leroy-Ladurie, F. Vaylet, I. Rouquette, P. Validire, M. Beau-Faller, L. Lacroix, J.C. Soria, P. Fouret
Journal: Annals of Oncology (2011)
Standardised work-up programme for fever of unknown origin and contribution of magnetic resonance imaging for the diagnosis of hidden systemic vasculitis
Authors: A D Wagner
Journal: Annals of the Rheumatic Diseases (2004)

<b>Background:</b> Fever of unknown origin (FUO) is a diagnostic challenge. Rheumatologists are often in charge of patients with FUO because the vasculitides, especially, are potential and common causes of FUO. <b>Objective:</b> To evaluate the value of a standardised investigation to identify the cause of FUO. <b>Methods:</b> A standardised work-up programme for patients with FUO was started at the beginning of September 1999. The rate of identified causes of FUO was compared between all patients with FUO admitted to a tertiary care centre of rheumatology between January 1996 and August 1999 (control group) and September 1999 and January 2003 (work-up group). In January 2002 magnetic resonance imaging (MRI) was added to the investigation. <b>Results:</b> 67 patients with FUO were identified—32 before and 35 after institution of the work-up programme. Before implementation 25% of all patients with FUO remained undiagnosed, after implementation 37%. After institution of the investigation the percentage of patients with vasculitides increased significantly from 6% (n = 2) to 26% (n = 9, p = 0.047, Fisher's exact test). This increase could be attributed to the addition of MRI in 2002. When all patients with FUO before 2002 (n = 55) and thereafter (n = 12) were compared the prevalence of systemic vasculitis increased from 11% (n = 6) to 42% (n = 5, p = 0.021). <b>Conclusion:</b> Implementation of a standardised work-up programme for FUO did not improve the overall rate of diagnosis. Addition of MRI significantly increased the diagnosis of systemic vasculitis as the underlying cause of FUO. MRI should be included in the investigation of patients with FUO when vasculitis is suspected.
Cardiac Malformations Associated with Down's Syndrome
Authors: RAJENDRA TANDON, JESSE E. EDWARDS
Journal: Circulation (1973)

A review of 55 specimens with congenital heart disease from subjects with Down's syndrome (Mongolism) showed a variety of malformations. For each case a major anomaly was identified and, when present, additional anomalies were recorded. The three leading types of major anomalies, in order of decreasing frequency, were (1) persistent common atrioventricular canal (60%), isolated ventricular septal defect (29%), and tetralogy of Fallot either alone or in association with persistent common atrioventricular canal (14.5%). Of the additional anomalies, the most common took the form either of an atrial septal defect at the fossa ovalis (50%) or patent ductus arteriosus (47%).