tbuckley/cabot-search huggingface dataset:
A Randomized Phase II Trial of the Antiangiogenic Agent SU5416 in Hormone-Refractory Prostate Cancer
Authors: Walter M. Stadler, Dingcai Cao, Nicholas J. Vogelzang, Christopher W. Ryan, Kristin Hoving, Russell Wright, Theodore Karrison, Everett E. Vokes
Journal: Clinical Cancer Research (2004)

Abstract Purpose: To assess the activity of the antiangiogenic agent and VEGFR2 inhibitor SU5416 in hormone-refractory prostate cancer. Patients and Methods: Thirty-six chemotherapy naïve patients were randomized to treatment with SU5416 (145 mg/m2) and dexamethasone premedication or dexamethasone alone. Patients in the control arm could cross over to experimental therapy after progression. Prostate-specific antigen (PSA) was measured every 2 weeks, and radiological evaluation was performed every 8 weeks. In vitro assessment of SU5416 on PSA secretion was assessed in the LNCaP cell line. Baseline serum basic fibroblast growth factor and plasma vascular endothelial growth factor (VEGF) were explored as prognostic factors. Results: VEGF receptor-2 expression is detectable in prostate cancer cell lines, and SU5416 inhibited in vitro PSA secretion. No effect of SU5416 on PSA secretion or time to progression is detectable in patients. VEGF and basic fibroblast growth factor were not prognostic. Headache and fatigue were the most common SU5416 toxicities, but hyperglycemia, hyponatremia, lymphopenia, infection, and adrenal suppression, all attributable to steroids and the required central line, were common. Conclusion: No disease modifying effects of SU5416 were detectable in this small study. Modest toxicity, an inconvenient administration schedule, and availability of other VEGFR-targeted agents support the decision to halt further evaluation of SU5416 in prostate cancer.
Comparative analyses of Legionella species identifies genetic features of strains causing Legionnaires’ disease
Authors: Laura Gomez-Valero, Christophe Rusniok, Monica Rolando, Mario Neou, Delphine Dervins-Ravault, Jasmin Demirtas, Zoe Rouy, Robert J Moore, Honglei Chen, Nicola K Petty, Sophie Jarraud, Jerome Etienne, Michael Steinert, Klaus Heuner, Simonetta Gribaldo, Claudine Médigue, Gernot Glöckner, Elizabeth L Hartland, Carmen Buchrieser
Journal: Genome biology (2014)

Abstract Background The genus Legionella comprises over 60 species. However, L. pneumophila and L. longbeachae alone cause over 95% of Legionnaires’ disease. To identify the genetic bases underlying the different capacities to cause disease we sequenced and compared the genomes of L. micdadei , L. hackeliae and L. fallonii (LLAP10), which are all rarely isolated from humans. Results We show that these Legionella species possess different virulence capacities in amoeba and macrophages, correlating with their occurrence in humans. Our comparative analysis of 11 Legionella genomes belonging to five species reveals highly heterogeneous genome content with over 60% representing species-specific genes; these comprise a complete prophage in L. micdadei , the first ever identified in a Legionella genome. Mobile elements are abundant in Legionella genomes; many encode type IV secretion systems for conjugative transfer, pointing to their importance for adaptation of the genus. The Dot/Icm secretion system is conserved, although the core set of substrates is small, as only 24 out of over 300 described Dot/Icm effector genes are present in all Legionella species. We also identified new eukaryotic motifs including thaumatin, synaptobrevin or clathrin/coatomer adaptine like domains. Conclusions Legionella genomes are highly dynamic due to a large mobilome mainly comprising type IV secretion systems, while a minority of core substrates is shared among the diverse species. Eukaryotic like proteins and motifs remain a hallmark of the genus Legionella . Key factors such as proteins involved in oxygen binding, iron storage, host membrane transport and certain Dot/Icm substrates are specific features of disease-related strains.
Chemical inactivation of HIV on surfaces.
Authors: P. J. Hanson, D. Gor, D. J. Jeffries, J. V. Collins
Journal: BMJ (1989)

To assess whether alcohol and glutaraldehyde are effective disinfectants against dried HIV the virucidal effects of 70% alcohol (ethanol and industrial methylated spirit) and 1% and 2% alkaline glutaraldehyde were tested against cell associated and cell free HIV dried on to a surface. Virus stock (100 microliters) or 10,000 cultured C8166 T lymphocytes infected with HIV were dried onto sterile coverslips and immersed in 2% and 1% alkaline glutaraldehyde and 70% ethanol for 30 seconds and one, two, four, and 10 minutes, there being an additional time point of 20 minutes for cell free virus disinfected with 70% industrial methylated spirit. In addition, virus stock in neat serum was tested with 1% and 2% alkaline glutaraldehyde to see whether the fixative properties of glutaraldehyde impair its virucidal properties. Virus activity after disinfection was tested by incubating the coverslips (cell associated virus) or the coverslips and sonicated cell free virus with C8166 T lymphocytes. The lymphocytes were examined for the formation of syncytia and HIV antigens were assayed in the culture fluid. Both 2% and 1% alkaline glutaraldehyde inactivated cell free HIV within one minute; 2% alkaline glutaraldehyde also inactivated cell free virus in serum within two minutes, but a 1% solution was ineffective after 15 minutes9 immersion. Cell associated HIV was inactivated by 2% alkaline glutaraldehyde within two minutes. Seventy per cent industrial methylated spirit failed to inactivate cell free and cell associated HIV within 20 and 15 minutes, respectively, and 70% ethanol did not inactivate cell free virus within 10 minutes. Seventy per cent industrial methylated spirit and ethanol are not suitable for surface disinfection of HIV. Fresh 2% solutions of alkaline glutaraldehyde are effective, but care should be taken that they are not too dilute or have not become stale when used for disinfecting HIV associated with organic matter.
Therapeutic Decision-making for Sleep Apnea and Hypopnea Syndrome Using Home Respiratory Polygraphy
Authors: Juan F. Masa, Jaime Corral, Ricardo Pereira, Joaquin Duran-Cantolla, Marta Cabello, Luis Hernández-Blasco, Carmen Monasterio, Alberto Alonso, Eusebi Chiner, Jose Zamorano, Felipe Aizpuru, Jose M. Montserrat
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Rationale: Home respiratory polygraphy (HRP) is an alternative to polysomnography (PSG) for sleep apnea–hypopnea syndrome (SAHS) diagnosis. However, therapeutic decision-making is a different process than diagnosis.Objectives: This study aimed to determine the agreement between HRP and in-hospital PSG for therapeutic decision-making in a large sample.Methods: Patients with an intermediate or high SAHS suspicion were included in a multicenter study (eight sleep centers) and assigned to home and hospital protocols in a random order. Therapeutic decisions (continuous positive airway pressure, no continuous positive airway pressure, or impossible decision) were made by an investigator in each center, based on using either HRP or PSG and a single set of auxiliary clinical variables. Patients and diagnostic methods (HRP and PSG) were assessed in random order using an electronic database. After a month the same therapeutic decision-making procedure was repeated with the same method.Measurements and Main Results: Of 366 randomized patients, 348 completed the protocol. The "impossible decision" case was not observed with either PSG or HRP. Therapeutic decisions using HRP had a sensitivity of 73%, a specificity of 77%, and an agreement level (sum of true positives and negatives) of 76%. Patients with higher HRP apnea–hypopnea index (AHI) scores (≥ 30; 41% of the total sample) had a sensitivity of 94%, a specificity of 44%, and the agreement level was 91%.Conclusions: The HRP-based therapeutic decision was adequate when AHI was high, but deficient in the large population of patients with mild to moderate AHI. Therefore, both selecting patients with a high suspicion and severity of SAHS and future prospective cost-effectiveness studies are necessary.
Clinical characteristics and outcomes of therapy-related chronic myelomonocytic leukemia
Authors: Koichi Takahashi, Naveen Pemmaraju, Paolo Strati, Graciela Nogueras-Gonzalez, Jing Ning, Carlos Bueso-Ramos, Rajyalakshmi Luthra, Sherry Pierce, Jorge Cortes, Hagop Kantarjian, Guillermo Garcia-Manero
Journal: Blood (2013)
Fine-mapping of IgE associated loci 1q23, 5q31 and 12q13
Authors: Vishwas Sharma, Sven Michel, Vincent Gaertner, Andre Franke, Christian Vogelberg, Andrea von Berg, Albrecht Bufe, Andrea Heinzmann, Otto Laub, Ernst Rietschel, Burkhard Simma, Thomas Frischer, Jon Genuneit, Sonja Zeilinger, Thomas Illig, Michaela Schedel, Daniel Potaczek, Michael Kabesch
Journal: European Respiratory Journal (2014)

Background: Three loci influencing total serum IgE levels 1q23 ( FCER1A ), 5q31 ( RAD50 - IL13 and IL4 ) and 12q13 ( STAT6 ) were repeatedly identified by genome-wide association studies (GWAS). In order to determine causal variants which may have been missed by the GWAS, we performed fine-mapping and subsequent re-genotyping of the three loci taking also 1000 Genomes Project datasets into account.

Methods: Selection criteria for polymorphisms to be re-genotyped (MALDI-TOF-MS of 40 polymorphisms) in at least 1,303 German children (651 asthmatics) were based on linkage disequilibrium and putative functional relevance. Overall the effect of 64 polymorphisms (24 polymorphisms were available due to previous array genotyping) on total serum IgE, IgE percentiles and atopic diseases were assessed. Gene by gene interaction was analyzed using a risk score model. Additionally, in silico studies on functional effects of putative causal variants from these three loci were performed.

Results: We could confirm and extend previous GWAS findings. Interestingly different association patterns between the three loci were identified. While for 1q23 and 5q31 the majority of associations were found with mild to moderately elevated IgE levels, the SNPs of the 12q13 locus were associated with strongly elevated IgE levels. Gene by gene interaction analyses suggested an up to 4-fold increased risk for elevated IgE if mutations in all three loci are present.

Conclusion: In addition to the confirmation of previous results, novel associations of SNPs in 1q23, 5q31 and 12q13 with different levels of serum IgE and their concomitant contribution to IgE regulation were identified.
H-2-restricted cytotoxic effectors generated in vitro by the addition of trinitrophenyl-conjugated soluble proteins
Authors: A Schmitt-Verhulst, CB Pettinelli, PA Henkart, JK Lunney, GM Shearer
Journal: The Journal of Experimental Medicine (1978)

Murine spleen cells from normal donors were cultured in vitro with trinitrobenzene sulfonate (TNBS)-conjugated soluble proteins, i.e., bovine gamma globulin (TNP-BGG) or bovine serum albumin (TNP-BSA). Addition of 100 mug of any of these TNP-proteins to the spleen cell cultures led to the generation of cytotoxic T-cell effectors which were H-2-restricted and TNP- specific. The lytic potential of such effectors was comparable to that generated by sensitization with TNBS-modified syngeneic cells, and was restricted to haplotypes shared at the K or K plus I-A, or the D regions of the H-2 complex. Greater effecter cell activity was generated by addition of TNP-BGG against TNBS-modified targets which shared K plus I-A than against modified targets which shared the D region with the responding cells, which suggests that the same immune response genes are involved when the response is generated by the addition of TNP-conjugated soluble proteins or of TNBS- modified cells. H-2-restricted, TNP-specific effecter cells were generated by culturing mouse spleen cells with syngeneic cells which had been preincubated with TNP- BGG or TNP-BSA for 1.5 h. The addition of unconjugated soluble proteins to the cultures did not result in cytotoxic effectors detectable on H-2-matched targets, whether the targets were prepared by modification with TNBS, or by incubation with either the unconjugated or TNP-conjugated proteins. Depletion of phagocytic cells in the tumor preparation by Sephadex G-10 column fractionation before incubation with TNP-BSA had no effect on their lysis by the relevant effector cells. Immunofluorescent staining of tumor target cells with anti-TNP antibodies indicated that TNP could be detected on the tumor cells within 10 rain of incubation with TNP-BSA. The cytotoxic response generated by addition of the TNP-proteins to spleen cell cultures was found to be T-cell dependent at the effector phase, as shown by the sensitivity of the lytic phase to absorbed RAMB and complement. Furthermore, the response did not appear to be attributable to antibody-dependent cellular cytotoxicity. Three mechanisms were considered which could account for the generation of H-2-restricted, TNP-specific, cytotoxic T-cell effectors by the addition of soluble TNP-proteins. These include covalent linkage of activated TNP groups from the soluble proteins to cell surface components, macrophage processing of the soluble conjugates and presentation to the responding lymphocytes in association with H-2-coded self structures, or hydrophobic interaction of the TNP-proteins to cell surfaces. Results obtained from sodium dodecyl sulfate gel patterns indicating that cell-bound TNP was still linked to BSA, and the observation that phagocytic-depleted cells could interact with the soluble TNP-proteins and function as H-2-restricted targets, appear not to favor the first two proposed mechanisms.
Arrested B Lymphopoiesis and Persistence of Activated B Cells in Adult Interleukin 7−/− Mice
Authors: Thiago L. Carvalho, Tomaz Mota-Santos, Ana Cumano, Jocelyne Demengeot, Paulo Vieira
Journal: The Journal of Experimental Medicine (2001)

Interleukin 7 is a crucial factor for the development of murine T and B lymphocytes. We now report that, in the absence of interleukin 7, B lymphocyte production takes place exclusively during fetal and perinatal life, ceasing after 7 wk of age. In peripheral organs, however, the pool of B lymphocytes is stable throughout adult life and consists only of cells that belong to the B1 and marginal zone (MZ) compartments. This is accompanied by a 50-fold increase in the frequency of immunoglobulin (Ig)M- and IgG-secreting cells, and the concentration of serum immunoglobulins is increased three- to fivefold. Both the MZ phenotype and the increase in serum IgM are T cell independent. These findings reveal a previously undescribed pathway of B lymphopoiesis that is active in early life and is interleukin 7 independent. This pathway generates B1 cells and a normal sized MZ B lymphocyte compartment.
Enhanced Postischemic Functional Recovery in CYP2J2 Transgenic Hearts Involves Mitochondrial ATP-Sensitive K <sup>+</sup> Channels and p42/p44 MAPK Pathway
Authors: John Seubert, Baichun Yang, J. Alyce Bradbury, Joan Graves, Laura M. Degraff, Scott Gabel, Rebecca Gooch, Julie Foley, John Newman, Lan Mao, Howard A. Rockman, Bruce D. Hammock, Elizabeth Murphy, Darryl C. Zeldin
Journal: Circulation Research (2004)

Human CYP2J2 is abundant in heart and active in the biosynthesis of epoxyeicosatrienoic acids (EETs); however, the functional role of this P450 and its eicosanoid products in the heart remains unknown. Transgenic mice with cardiomyocyte-specific overexpression of CYP2J2 were generated. CYP2J2 transgenic (Tr) mice have normal heart anatomy and basal contractile function. CYP2J2 Tr hearts have improved recovery of left ventricular developed pressure (LVDP) compared with wild-type (WT) hearts after 20 minutes ischemia and 40 minutes reperfusion. Perfusion with the selective P450 epoxygenase inhibitor N -methylsulphonyl-6-(2-proparglyloxyphenyl)hexanamide (MS-PPOH) for 20 minutes before ischemia results in reduced postischemic LVDP recovery in WT hearts and abolishes the improved postischemic LVDP recovery in CYP2J2 Tr hearts. Perfusion with the ATP-sensitive K + channel (K ATP ) inhibitor glibenclamide (GLIB) or the mitochondrial K ATP (mitoK ATP ) inhibitor 5-hydroxydecanoate (5-HD) for 20 minutes before ischemia abolishes the cardioprotective effects of CYP2J2 overexpression. Flavoprotein fluorescence, a marker of mitoK ATP activity, is higher in cardiomyocytes from CYP2J2 Tr versus WT mice. Moreover, CYP2J2-derived EETs (1 to 5 μmol/L) increase flavoprotein fluorescence in WT cardiomyocytes. CYP2J2 Tr mice exhibit increased expression of phospho-p42/p44 mitogen-activated protein kinase (MAPK) after ischemia, and addition of the p42/p44 MAPK kinase (MEK) inhibitor PD98059 during reperfusion abolishes the cardioprotective effects of CYP2J2 overexpression. Together, these data suggest that CYP2J2-derived metabolites are cardioprotective after ischemia, and the mechanism for this cardioprotection involves activation of mitoK ATP and p42/p44 MAPK.
Vascular Endothelial Growth Factor (VEGF) Expression in Human Coronary Atherosclerotic Lesions
Authors: Mayumi Inoue, Hiroshi Itoh, Makiko Ueda, Takahiko Naruko, Akiko Kojima, Ryushi Komatsu, Kentaro Doi, Yoshihiro Ogawa, Naohisa Tamura, Kazuhiko Takaya, Toshio Igaki, Jun Yamashita, Tae-Hwa Chun, Ken Masatsugu, Anton E. Becker, Kazuwa Nakao
Journal: Circulation (1998)

Background —Vascular endothelial growth factor (VEGF) is an important angiogenic factor reported to induce migration and proliferation of endothelial cells, enhance vascular permeability, and modulate thrombogenicity. VEGF expression in cultured cells (smooth muscle cells, macrophages, endothelial cells) is controlled by growth factors and cytokines. Hence, the question arises of whether VEGF could play a role in atherogenesis. Methods and Results —Frozen sections from 38 coronary artery segments were studied. The specimens were characterized as normal with diffuse intimal thickening, early atherosclerosis with hypercellularity, and advanced atherosclerosis (atheromatous plaques, fibrous plaques, and totally occlusive lesions). VEGF expression as well as the expression of 2 VEGF receptors, flt-1 and Flk-1, were studied with immunohistochemical techniques in these samples at the different stages of human coronary atherosclerosis progression. The expression of VEGF mRNA was also studied with reverse transcription–polymerase chain reaction. Normal arterial segments showed no substantial VEGF expression. Hypercellular and atheromatous lesions showed distinct VEGF positivity of activated endothelial cells, macrophages, and partially differentiated smooth muscle cells. VEGF positivity was also detected in endothelial cells of intraplaque microvessels within advanced lesions. In totally occlusive lesions with extensive neovascularization, intense immunostaining for VEGF was observed in accumulated macrophages and endothelial cells of the microvessels. Furthermore, VEGF mRNA expression was detected in atherosclerotic coronary segments but not in normal coronary segments. The immunostainings for flt-1 and Flk-1 were detected in aggregating macrophages in atherosclerotic lesions and also in endothelial cells of the microvessels in totally occlusive lesions. Conclusions —These results demonstrate distinct expression of VEGF and its receptors (flt-1 and Flk-1) in atherosclerotic lesions in human coronary arteries. Considering the multipotent actions of VEGF documented experimentally in vivo and in vitro, our findings suggest that VEGF may have some role in the progression of human coronary atherosclerosis, as well as in recanalization processes in obstructive coronary diseases.
Future Directions in Idiopathic Pulmonary Fibrosis Research. An NHLBI Workshop Report
Authors: Timothy S. Blackwell, Andrew M. Tager, Zea Borok, Bethany B. Moore, David A. Schwartz, Kevin J. Anstrom, Ziv Bar-Joseph, Peter Bitterman, Michael R. Blackburn, William Bradford, Kevin K. Brown, Harold A. Chapman, Harold R. Collard, Gregory P. Cosgrove, Robin Deterding, Ramona Doyle, Kevin R. Flaherty, Christine Kim Garcia, James S. Hagood, Craig A. Henke, Erica Herzog, Cory M. Hogaboam, Jeffrey C. Horowitz, Talmadge E. King, James E. Loyd, William E. Lawson, Clay B. Marsh, Paul W. Noble, Imre Noth, Dean Sheppard, Julie Olsson, Luis A. Ortiz, Thomas G. O’Riordan, Tim D. Oury, Ganesh Raghu, Jesse Roman, Patricia J. Sime, Thomas H. Sisson, Daniel Tschumperlin, Shelia M. Violette, Timothy E. Weaver, Rebecca G. Wells, Eric S. White, Naftali Kaminski, Fernando J. Martinez, Thomas A. Wynn, Victor J. Thannickal, Jerry P. Eu
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

Section:ChooseTop of pageAbstract <<Biology of Alveolar Injur...Role of ECMPreclinical ModelingThe Role of Inflammation ...Genetic, Epigenetic, and ...Translation of Discoverie...SummaryReferencesCITING ARTICLES
American Researchers Question Effect of Scandinavian Mammography Debate
Authors: R. Twombly
Journal: JNCI Journal of the National Cancer Institute (2007)

Apublic row is taking place among some European investigators over a 22-year-old study that helped lay the foundation for mammography screening worldwide. Some experts question if it could — or even should — affect current practice in the United States. The dispute centers on the Swedish two-county trial, which reported the largest reduction in breast cancer deaths found in all of the seven randomized mammography screening trials conducted around the world — a 31% decline. Enrolling more than 134,000 women, the 1985 report in The Lancet remains the largest clinical study of the power
Serum Immunoglobulin Levels in Healthy Thai Infants and Children Aged 0-2 Years Determined by Nephelometry
Authors: R. Sitcharungsi, J. Ananworanich, A. Pornvoranunt, T. Apornpong, T. Bunupuradah, K. Khupulsup, P. Nouanthong, S. Vilaiyuk, C. Phasomsap, W. Kamchaisatian, C. Pancharoen, T. Puthanakit, C. Sirivichayakul, S. Benjaponpitak
Journal: Journal of Allergy and Clinical Immunology (2012)
Cdk2 is Required for Breast Cancer Mediated by the Low-Molecular-Weight Isoform of Cyclin E
Authors: Said Akli, Carolyn S. Van Pelt, Tuyen Bui, Laurent Meijer, Khandan Keyomarsi
Journal: Cancer Research (2011)

Cyclin E activates Cdk2, controls centrosome duplication, and regulates histone gene transcription. Cyclin E is deregulated in cancer and appears as low-molecular-weight (LMW) isoforms that correlate strongly with decreased survival in breast cancer patients. Transgenic mice overexpressing LMW-cyclin E have increased incidence of mammary tumors and distant metastasis when compared with mice that had full-length cyclin E. To specifically test the requirement for Cdk2 in LMW-cyclin E-mediated mammary tumorigenesis, we generated transgenic mice, which expressed LMW-cyclin E in a Cdk2-deficient background. We found that mammary gland development proceeds relatively normally in these animals, indicating that Cdk2 kinase activity is largely dispensable for this process. However, Cdk2-deficient mice were completely resistant to LMW-cyclin E-mediated mammary tumors. Cdk2 wild-type or heterozygous mice succumbed to mammary tumors with mean latencies of 16 and 19.5 months, respectively, but Cdk2 nullizygous littermates did not display tumors through 24 months. Similarly, continuous administration of two different Cdk inhibitors significantly delayed LMW-cyclin E-induced mammary tumor progression. Triple transgenic mice generated in a p53 heterozygous background also displayed no tumors. Finally, we found that Cdk2 silencing induced cell death in LMW-overexpressing breast cancer cell lines, but not in cell lines lacking LMW expression. Our findings establish a requirement for Cdk2 in LMW-cyclin E-mediated mammary tumorigenesis, arguing that human breast tumors overexpressing LMW-cyclin E are prime candidates for anti-Cdk2 therapy.