tbuckley/cabot-search huggingface dataset:
Pleiotropic effects of antithrombin strand 1C substitution mutations.
Authors: D A Lane, R J Olds, J Conard, M Boisclair, S C Bock, M Hultin, U Abildgaard, H Ireland, E Thompson, G Sas
Journal: Journal of Clinical Investigation (1992)

Six different substitution mutations were identified in four different amino acid residues of antithrombin strand 1C and the polypeptide leading into strand 4B (F402S, F402C, F402L, A404T, N405K, and P407T), and are responsible for functional antithrombin deficiency in seven independently ascertained kindreds (Rosny, Torino, Maisons-Laffitte, Paris 3, La Rochelle, Budapest 5, and Oslo) affected by venous thromboembolic disease. In all seven families, variant antithrombins with heparin-binding abnormalities were detected by crossed immunoelectrophoresis, and in six of the kindreds there was a reduced antigen concentration of plasma antithrombin. Two of the variant antithrombins, Rosny and Torino, were purified by heparin-Sepharose and immunoaffinity chromatography, and shown to have greatly reduced heparin cofactor and progressive inhibitor activities in vitro. The defective interactions of these mutants with thrombin may result from proximity of s1C to the reactive site, while reduced circulating levels may be related to s1C proximity to highly conserved internal beta strands, which contain elements proposed to influence serpin turnover and intracellular degradation. In contrast, s1C is spatially distant to the positively charged surface which forms the heparin binding site of antithrombin; altered heparin binding properties of s1C variants may therefore reflect conformational linkage between the reactive site and heparin binding regions of the molecule. This work demonstrates that point mutations in and immediately adjacent to strand 1C have multiple, or pleiotropic, effects on this serpin, leading ultimately to failure of its regulatory function.
Increased urinary type II collagen helical and C telopeptide levels are independently associated with a rapidly destructive hip osteoarthritis
Authors: P Garnero, N Charni, F Juillet, T Conrozier, E Vignon
Journal: Annals of the Rheumatic Diseases (2006)

Biochemical markers reflecting the degradation of the type II collagen helical (Helix-II) and type II collagen C telopeptides (CTX-II) have been developed.
Development of a Novel Method for Cell Transplantation Through the Coronary Artery
Authors: K. Suzuki, N. J. Brand, R. T. Smolenski, J. Jayakumar, B. Murtuza, M. H. Yacoub
Journal: Circulation (2000)

Cell transplantation is a promising strategy to treat end-stage heart failure. At present, a popular method to deliver cells into the heart is direct intramuscular injection. This method, however, may not be efficient in spreading cells globally into the myocardium. We have developed a novel method for cell transplantation using intracoronary infusion.An L6 rat skeletal muscle cell line expressing ss-galactosidase (ss-gal) was generated by gene transfection and clonal selection. These cells (10(6) in 1 mL medium) were infused into explanted rat hearts through the coronary artery, followed by heterotopic heart transplantation into the abdomen of recipients. Control hearts were infused with cell-free medium. According to ss-gal activity measurements, approximately 5 x 10(5) grafted cells per heart existed on day 3, increasing to 5 x 10(6) on day 28 in the cell-transplanted hearts. At day 28, discrete loci positively stained for ss-gal were observed throughout the cardiac layers of both left and right coronary territories. Some of them differentiated into ss-gal-positive multinucleated myotubes that aligned with the cardiac fiber axis and integrated into the native myocardium, whereas others formed colonies consisting of undifferentiated myoblasts. Connexin 43, a cardiac gap junction protein, was expressed between grafted cells and native cardiomyocytes. No reduction in cardiac function was observed in a Langendorff perfusion system.We have developed a unique method for efficient cell transplantation based on intracoronary infusion. This method, potentially applicable in the clinical setting during cardiac surgery, could be useful to globally supply cells to the heart.
Eosinophil degranulation status in allergic rhinitis: observations before and during seasonal allergen exposure
Authors: C.A. Ahlstrom-Emanuelsson, L. Greiff, M. Andersson, C.G.A. Persson, J.S. Erjefält
Journal: European Respiratory Journal (2004)

Despite the fact that extensive degranulation is a likely prerequisite for a pathogenic role of eosinophils, little is known about the degranulation status of these cells in eosinophilic conditions. The present study of the ultrastructure of tissue eosinophils explores eosinophil degranulation in allergic rhinitis before and during seasonal allergen exposure. A total of 23 patients scored symptoms q.d. , prior to and during the pollen season. The numbers of mucosal eosinophils and their degranulation status were determined in nasal biopsies. Furthermore, nasal lavage fluid levels of eosinophil cationic protein (ECP) and α 2 -macroglobulin were assessed as indices of eosinophil activity and plasma exudation, respectively. Seasonal allergen exposure was associated with increased nasal symptoms, increased lavage fluid levels of ECP and α 2 -macroglobulin, and increased numbers of tissue eosinophils. In the tissue, transmission electron microscopy revealed a moderate piecemeal degranulation already prior to the season (mean± sd 37±2.7% altered granules). Seasonal allergen exposure increased this degranulation (87±1.8%), and produced local areas with extensive deposition of granule proteins. The degree of eosinophil degranulation correlated with levels of ECP in lavage fluids obtained at histamine challenge. In conclusion, this study demonstrated that the nasal mucosa in allergic rhinitis features moderately degranulated eosinophils already at nonsymptomatic baseline conditions. In association with the development of symptomatic seasonal allergic rhinitis, the tissue deposition of eosinophil granule proteins is dramatically elevated through increased eosinophil numbers, together with markedly augmented degranulation of individual cells.
Insertion of c-<i>Myc</i>into<i>Igh</i>Induces B-Cell and Plasma-Cell Neoplasms in Mice
Authors: Sung Sup Park, Joong Su Kim, Lino Tessarollo, James D. Owens, Liangping Peng, Seong Su Han, Seung Tae Chung, Ted A. Torrey, Wan C. Cheung, Roberto D. Polakiewicz, Nicole McNeil, Thomas Ried, J. Frederic Mushinski, Herbert C. Morse, Siegfried Janz
Journal: Cancer Research (2005)

We used gene targeting in mice to insert a His(6)-tagged mouse c-Myc cDNA, Myc(His), head to head into the mouse immunoglobulin heavy-chain locus, Igh, just 5' of the intronic enhancer, Emu. The insertion of Myc(His) mimicked both the human t(8;14)(q24;q32) translocation that results in the activation of MYC in human endemic Burkitt lymphomas and the homologous mouse T(12;15) translocation that deregulates Myc in certain mouse plasmacytomas. Beginning at the age of 6 months, Myc(His) transgenic mice developed B-cell and plasma neoplasms, such as IgM(+) lymphoblastic B-cell lymphomas, Bcl-6(+) diffuse large B-cell lymphomas, and CD138(+) plasmacytomas, with an overall incidence of 68% by 21 months. Molecular studies of lymphoblastic B-cell lymphoma, the most prevalent neoplasm (50% of all tumors), showed that the lymphomas were clonal, overexpressed Myc(His), and exhibited the P2 to P1 promoter shift in Myc expression, a hallmark of MYC/Myc deregulation in human endemic Burkitt lymphoma and mouse plasmacytoma. Only 1 (6.3%) of 16 lymphoblastic B-cell lymphomas contained a BL-typical point mutation in the amino-terminal transactivation domain of Myc(His), suggesting that most of these tumors are derived from naive, pregerminal center B cells. Twelve (46%) of 26 lymphoblastic B-cell lymphomas exhibited changes in the p19(Arf)-Mdm2-p53 tumor suppressor axis, an important pathway for Myc-dependent apoptosis. We conclude that Myc(His) insertion into Igh predictably induces B-cell and plasma-cell tumors in mice, providing a valuable mouse model for understanding the transformation-inducing consequences of the MYC/Myc-activating endemic Burkitt lymphoma t(8;14)/plasmacytoma T(12;15) translocation.
Human immunodeficiency virus infection of eosinophils in human bone marrow cultures.
Authors: A R Freedman, F M Gibson, S C Fleming, C J Spry, G E Griffin
Journal: The Journal of Experimental Medicine (1991)

Normal human bone marrow, cultured in vitro with interleukin 5 to promote eosinophil production and maturation, was inoculated with cell-free isolates of human immunodeficiency virus type 1 (HIV-1). CD4 expression by eosinophil precursors, determined by immunocytochemistry, was found to be greatest early in their maturation with a rapid decline after 28 d in culture. Productive HIV infection of eosinophil precursors was detected 14 d after inoculation, by a combination of immunostaining for HIV-1 p24 and gp41/160 and in situ hybridization for viral RNA, together with assay of culture supernatants for p24 antigen and reverse transcriptase activity. Thus, eosinophils are susceptible to productive HIV-1 infection in vitro and may be an important reservoir for the virus in vivo.
Statins in the treatment of chronic heart failure: Biological and clinical considerations
Authors: P VANDERHARST, A VOORS, W VANGILST, M BOHM, D VANVELDHUISEN
Journal: Cardiovascular Research (2006)

Patients with increased cholesterol levels are at increased risk to experience cardiovascular events and to die from vascular disease. Statins have been proven to effectively reduce cholesterol levels and subsequently reduce cardiovascular events in patients with coronary artery disease or at increased risk to develop coronary artery disease. However, in patients with chronic heart failure (CHF), not high, but low levels of cholesterol are related to increased mortality. This phenomenon of reverse epidemiology is not unique to CHF, but also exists in other critical diseases and in the elderly in general as well. An important rationale has been provided by the endotoxin hypothesis, which suggests that cholesterol has an important scavenger function regarding harmful endotoxins. Indeed, these lines of evidence predict a harmful effect of statin treatment in patients with CHF. However, statins not only lower cholesterol, but also have been reported to exhibit a plethora of pleiotropic effects, including reduction of inflammation and improvement of endothelial function. In order to reconcile these contradictory lines of evidence, it is necessary to examine the pharmacological mechanisms of effects of statin treatment. Understanding the pharmacology of statin intervention in CHF models and patients may facilitate the development of therapeutic strategies. In this review, we provide an overview of the known associations between serum cholesterol and CHF in human subjects. In addition, we review the available lines of evidence in animal models and humans predicting both harmful and beneficial effects of statin treatment in CHF. We emphasize the importance of additional research specifically in CHF models and patients.
Possible immunotherapeutic potentiation with D-Fraction in prostate cancer cells
Authors: Paul Pyo, Brandon Louie, Srinivas Rajamahanty, Muhammad Choudhury, Sensuke Konno
Journal: Journal of Hematology & Oncology (2008)

Abstract Background Prostate cancer remains the most common malignancy among elderly men and the second leading cause of cancer death in the United States. Although several conventional therapies are currently available, they have a low efficacy and the more effective treatment modalities need to be established. Interferons (IFNs) are one of such options known as immunotherapy and demonstrated their antitumor effects on certain cancer types. Yet such antitumor activity should be improved or potentiated to have the satisfactory outcomes. In fact, combination therapy has been proposed as an alternative approach and is being underway in human and animal studies. Accordingly, we studied whether the combination of IFN-α and D-fraction (PDF), a bioactive mushroom extract, might potentiate anticancer activity of IFN-α in prostate cancer PC-3 cells in vitro . Results Potential effects of recombinant IFN-α 2b (0–100,000 IU/ml), PDF (0–1,000 μg/ml), or their combinations were assessed on the growth of PC-3 cells at 72 h. Cell cycle analysis using a flow cytometer and Western blot analysis were performed to explore antiproliferative mechanism of these agents. The dose-dependent study showed that IFN-α 2b up to 20,000 (20 K) IU/ml had no significant effects, but &gt;60% growth reduction was attained ≤50 K IU/ml. Similarly, PDF showed no effects up to 250 μg/ml but ~65% growth reduction was seen at 1,000 μg/ml. When IFN-α 2b and PDF were combined, a relatively low concentration (10 K IU/ml) of IFN-α 2b and PDF (250 μg/ml) resulted in a ~65% growth reduction. This was accompanied by a G 1 cell cycle arrest, indicated by cell cycle analysis. Western blots also revealed that the G 1 -specific cell cycle regulators, CDK2, CDK4, CDK6, cyclin D 1 , and cyclin E, had been significantly (&gt;60%) down-regulated in IFN/PDF-treated cells. Conclusion The combination of IFN-α 2b (10 K IU/ml) and PDF (250 μg/ml) is capable of inducing a ~65% reduction in PC-3 cell growth. This appears to be due to a synergistic potentiation of two agents, leading to a G 1 cell cycle arrest. Thus, it is conceivable that PDF may potentiate IFN-α 2b activity, improving immunotherapy for prostate cancer.
N-terminal hevein-like domains (4.3 kDa) but not 31 kDa endochitinases are responsible for IgE-mediated in vitro and in vivo reactions in latex-fruit syndrome
Authors: P. Karisola, A. Kotovuori, S. Poikonen, E. Niskanen, N. Kalkkinen, K. Turjanmaa, T. Palosuo, T. Reunala, H. Alenius, M. Kulomaa
Journal: Journal of Allergy and Clinical Immunology (2005)
Prothrombin G20210A Mutant Genotype Is a Risk Factor for Cerebrovascular Ischemic Disease in Young Patients
Authors: Valerio De Stefano, Patrizia Chiusolo, Katia Paciaroni, Ida Casorelli, Elena Rossi, Marco Molinari, Serenella Servidei, Pietro A. Tonali, Giuseppe Leone
Journal: Blood (1998)
Evidence That Drugs in Multiple Combinations Have Materially Advanced the Treatment of Human Malignancies
Authors: Edward S. Henderson, Richard J. Samaha
Journal: Cancer Research (1969)

Is combination chemotherapy superior to single drug therapy in the treatment of cancer? The straightforwardness of this question, implicit in the title of this talk, belies its complexity. Lacking a simple explanation of cancer, I must dissect the query and my rejoinders into the many ramifications of treatment-its purpose, its phases, and its results-cognizant that no one conclusion, affirmative or negative, will of itself suffice. In the most general sense, combinations of therapies, whether drugs and/or other modalities, will always play an important role in the management of diseases for which there exists no single specific and totally effective treatment. When one treats patients with certain cancers, rheumatoid arthritis, hypertension, diabetes mellitus, or tuberculosis, to mention just a few examples, one is frequently unable to control the total disease process by any single means, and a cure is often unobtainable. Single agents may suffice during parts of the illness, but from time to time multiple agents are invaluable. In each instance the identification of a single, totally effective treatment would quickly render the combination obsolete, as has occurred with many bacterial infections and a handful of neoplasms. In other morbid conditions, for example, multiple sclerosis, infectious hepatitis, and most disseminated cancers, no therapy is known to definitely and specifically alter the natural course of the illness, and in these situations com binations have been equally unimpressive. These examples outline some of the indications for com bination therapy: (a) the illness does not regularly respond to any single form of treatment, but (b) it can be modified partially by at least two modalities of therapy. Combination chemotherapy has most frequently been explored in the treatment of leukemia, but it has also provided benefit in certain solid tumors. Evaluation of therapy in solid tumors, similar to comparative studies of leukemia chemo therapy, has been hampered in many studies by: (a) lack of sufficient suitable patients, (b) inability to determine the full extent of disease, (c) difficulty in establishing criteria of response, and (d) uncontrolled variation in dosage and spacing of therapeutic agents (such as radiation therapy). Despite the aforementioned handicaps, the use of combinations of drugs with or without radiation therapy has provided sufficient data in certain malignancies other than leukemia either to suggest or to prove the superiority of combined therapy versus single agents. In most instances, the duration of a complete objective response or tumor-free interval has been used as the criterion of effectiveness; however, in some studies, survival time has
The Universal Character of the Tumor-Associated Antigen Survivin
Authors: Mads Hald Andersen, Inge Marie Svane, Jürgen C. Becker, Per thor Straten
Journal: Clinical Cancer Research (2007)

Abstract Survivin is expressed in most human neoplasms, but is absent in normal, differentiated tissues. Survivin is a bifunctional inhibitor of apoptosis protein that has been implicated in protection from apoptosis and regulation of mitosis. Several clinical trials targeting survivin with a collection of different approaches from small molecule antagonists to immunotherapy are currently under way. With regard to the latter, spontaneous anti-survivin T-cell reactivity has been described in cancer patients suffering from a huge range of cancers of different origin, e.g., breast and colon cancer, lymphoma, leukemia, and melanoma. Thus, survivin may serve as a universal target antigen for anticancer immunotherapy. Accordingly, down-regulation of survivin as a means of immune escape would severely inflict the survival capacity of tumor cells, which highlights this protein as a prime target candidate for therapeutic vaccinations against cancer. Data from several ongoing phase I/II trials targeting survivin for patients with advanced cancer will provide further information about this idea.
Selective Induction of Apoptosis with Proton Pump Inhibitor in Gastric Cancer Cells
Authors: Marie Yeo, Dong-Kyu Kim, Young-Bae Kim, Tae Young Oh, Jong-Eun Lee, Sung Won Cho, Hugh Chul Kim, Ki-Baik Hahm
Journal: Clinical Cancer Research (2004)

Abstract Purpose: To survive in an ischemic microenvironment with a lower extracellular pH, ability to up-regulate proton extrusion is critical for cancer cell survival. Gastric H+/K+-ATPase exchanges luminal K+ for cytoplasmic H+ and is the enzyme primarily responsible for gastric acidification. On the basis of the fact that blocking the clearance of acidic metabolites are known to induce the cell death, we hypothesized that pantoprazole (PPZ), one of gastric H+/K+-ATPase inhibitors used frequently to treat acid-related diseases, could inhibit growth of tumor cells. Experimental Design: Genomic DNA fragmentation, terminal deoxynucleotidyl transferase (Tdt)-mediated nick end labeling assay, and annexin V staining were performed to detect PPZ-induced apoptosis. Mitogen-activated protein kinase activation and heat shock proteins expression were determined by immunoblot with specific antibodies. The antitumor effect of PPZ was evaluated in vivo by a xenograft model of nude mice. Results: After PPZ treatment, apoptotic cell death was seen selectively in cancer cells and was accompanied with extracellular signal-regulated kinase deactivation. By contrast, normal gastric mucosal cells showed the resistance to PPZ-induced apoptosis through the overexpression of antiapoptotic regulators including HSP70 and HSP27. In a xenograft model of nude mice, administration of PPZ significantly inhibited tumorigenesis and induced large-scale apoptosis of tumor cells. Conclusions: PPZ selectively induced in vivo and in vitro apoptotic cell death in gastric cancer, suggesting that proton pump inhibitors could be used for selective anticancer effects.
Risk for Perinatal HIV-1 Transmission According to Maternal Immunologic, Virologic, and Placental Factors
Authors: Michael E. St. Louis
Journal: JAMA (1993)

To evaluate how maternal and obstetric factors interact to influence mother-to-child human immunodeficiency virus type 1 (HIV-1) transmission.Prospective, observational cohort study of children born to HIV-infected women to determine child's HIV infection status. The analysis then compared peripartum maternal, placental, and obstetric variables between HIV-1 transmitter and nontransmitter women.Two large maternity wards in Kinshasa, Zaire.Consecutive sample of 324 HIV-1-infected women at delivery, with 254 HIV-seronegative women followed up as control subjects. PRINCIPAL OUTCOME MEASURES: HIV infection status of children, to classify each woman as an HIV-1 transmitter or nontransmitter.The highest transmission risk (TR) was associated with maternal p24 antigenemia (TR, 71%; relative risk [RR], 3.0; 95% confidence interval [CI], 1.7 to 5.2) and maternal CD8+ lymphocyte counts of at least 1.80 x 10(9)/L (1800/microL) (TR, 50%; RR, 2.2; 95% CI, 1.2 to 4.2). Among women with CD8+ lymphocyte counts of less than 1.80 x 10(9)/L, CD4+ lymphocyte counts of less than 0.60 x 10(9)/L were a risk factor (TR, 29%; RR, 2.2; 95% CI, 1.2 to 4.2). In women with neither high CD8+ nor low CD4+ lymphocyte counts, placental membrane inflammation was associated with perinatal transmission (TR, 40%; RR, 4.2; 95% CI, 1.3 to 13.7). In women with neither p24 antigenemia, high CD8+ or low CD4+ lymphocyte counts, nor placental membrane inflammation, the transmission risk was only 7%. Additional correlates of transmission included maternal anemia and fever, but not maternal sexually transmitted diseases.Identifiable subgroups of HIV-1-infected women based on maternal and placental characteristics had between a 7% and 71% risk of perinatal HIV-1 transmission. Not only the overall rate of transmission but the impact of different risk factors for transmission appear to vary over the course of HIV infection.